bluuebunny/crossref_metadata_2025 huggingface dataset:
The DEAL trial: A diet and exercise intervention in (pre)-diabetics during treatment for non-muscle invasive bladder cancer.
Authors: Smelser Woodson , Glazyrine Vassili , Barnes Brian , Stanley Abigail , Bechtel Misty , Michel Carrie , Holzbeierlein Jeffrey M. , Hamilton-Reeves Jill , Lee Eugene
Published: February 2018

473

Background: Patients with diabetes are at greater risk for bladder cancer (BC) as well as disease recurrence and progression. Even after controlling for clinical and pathologic risk factors, DM confers a 2x greater risk of recurrence and 9x greater risk of progression. We hypothesize that utilizing a carbohydrate restricted (CR) diet ( < 130 grams/day) to decrease the bioavailability of glucose in patients with DM and BC, a “Warburg-like” tumor, has potential therapeutic benefit. We designed a study to assess the feasibility of a CR diet in patients with (pre)diabetes and non-muscle invasive bladder cancer receiving BCG therapy. Methods: This is a pilot study of 5 (pre)diabetic patients (defined as HgbA1c > 5.7) with NMIBC receiving BCG and maintenance. A CR diet ( < 130 g/day) was supplied for the first 12 weeks through a meal delivery service. Patients received weekly coaching with a nutritionist for 6 weeks during induction BCG and at the 3 month surveillance cystoscopy with dietary and activity goals implemented. Patients had laboratory evaluation at baseline and at 3 month intervals. Patients tracked their diet. Two (1 weekday, 1 weekend day) unannounced 24 hour diet recalls were obtained to monitor compliance. Dietary compliance was defined as < 130 grams/day of carbohydrate intake. Results: Between 09/2016 and 05/2017, 5 patients were enrolled. Mean age was 66.2 years (Range 59-74). Three patients had diabetes and two patients had pre-diabetes. Two patients had CIS, 1 patient had high-grade Ta, and 2 patients had high-grade T1 disease. Mean baseline hemoglobin A1c was 7.6% (Range 5.9-11.8). Mean bodyweight and BMI were 92 kg (Range 66-105) and 28.2 (Range 23.1- 31.3) respectively. Regarding compliance, 4/5 (80%) patients completed dietary logs and weekly labs. Three patients (60%) achieved their goal of < 130 grams carbohydrates/day on 24-hour dietary recall. Average 3-month HbA1c improved from 7.6% to 6.6% (Range 5.6-7.9). Conclusions: Eighty percent of patients completed dietary logs for the first three months of the trial; 60% achieved compliance with the CR diet. These data demonstrate the feasibility of a dietary intervention utilizing CR in patients with high-grade NMIBC undergoing BCG. Clinical trial information: NCT02716623.
Evaluating cell cycle progression score as a prognostic marker for non-muscle invasive bladder cancer (NMIBC).
Authors: Weight Christopher J. , Murugan Paari J , Chesla David , Tejpaul Resha , Soubra Ayman , Boshoven William , Sangale Zaina , Rajamani Saradha , Stone Steven , Lane Brian R.
Published: February 2018

476

Background: Accurate grading and staging from transurethral resection of bladder tumors (TURBT) is vital for appropriate clinical management. Non-muscle-invasive bladder cancer (NMIBC) can recur progress with higher grade and or stage progression to MIBC, requiring radical intervention with poorer prognosis. Further, grade and stage may change in 20-50% of TURBTs following re-review by expert GU pathologists Objective measures of stage and grade might offer additional and/or improved risk stratification; therefore we evaluated a molecular RNA signature as a prognostic marker for NMIBC. Methods: Patients were diagnosed with NMIBC at the University of Minnesota (UM)or Spectrum Health System(SHS) from 2005-2012. A Cell Cycle Progression (CCP) score was determined from the average expression of 36 CCP genes for patients with available FFPE diagnostic TURBT. The combined cohort consisted of 293 patients (UM n = 152, SHS n = 141). Study outcome was time from NMIBC diagnosis to progression to MIBC. Median follow-up for patients who did not experience an event was 4.4 years for UM and 6.9 for SHS. Association with outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. All analyses were stratified by cohort. Results: CCP score was associated with progression to MIBC in univariable analysis [hazard ratio 1.42 (95% CI 1.19, 1.68), p = 4.3x10-5]. Tumor grade and stage were also highly prognostic. CCP score was strongly associated with stage (T1 vs Ta, p < 10-6) and grade (high vs low, p < 10-14) in both cohorts. As a result, CCP score did not provide independent prognostic information in multivariable analysis after adjusting for stage and grade (p = 0.32). There was a significant interaction between stage and CCP score (p = 0.0017), justifying an exploratory analysis of CCP score in Ta disease. In this subset, CCP score trended toward (p = 0.056) after adjusting for grade. Conclusions: In NMIBC, CCP score was highly correlated with tumor stage and grade and could serve as a quantitative measure of clinical parameters. The score may also provide prognostic information regarding risk of progression to MIBC, particularly in patients with Ta disease, but requires additional validation.
Association of upregulation of serine and one carbon metabolism genes with shorter recurrence-free and overall survival in urothelial bladder cancer (UBC).
Authors: Lattanzi Michael , Pacold Michael , Balar Arjun Vasant
Published: February 2018

477

Background: Antimetabolites (e.g. methotrexate and gemcitabine) are not frequently used in the treatment of most solid tumors, but are effective in the treatment of UBC. Rapid cancer cell proliferation relies on an abundance of serine-derived one carbon units to support macromolecule synthesis. Specifically, PHGDH, which encodes a key enzyme of de novo serine synthesis, is amplified in breast cancer and in melanoma, and small molecule inhibitors of enzymes in this pathway are in early clinical development. However, the enzymes of serine and one carbon metabolism have not been widely investigated in UBC. Methods: We conducted an observational analysis of The Cancer Genome Atlas UBC cohort, focusing on gene expression data from a targeted panel indicated by Yang, et al. to be involved in serine and one carbon metabolism. Univariate Cox proportional hazard models were utilized to identify genes impacting OS and RFS, and a subsequent multivariate model was employed to control for inter-gene associations. Results: Expression data from 14 genes were analyzed among 436 UBC patients, of whom complete data were available for 422. At a median follow-up of 17 months, 188 of 422 patients had died. On univariate analysis, 7 of 14 genes were significantly associated with OS: PHGDH, PSPH, MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 (all P < 0.05). Interestingly, overexpression was associated with worse OS for all but one gene, MTHFD2L (HR 0.74), which is known to be underexpressed by cancer cells in favor of MTHFD2 (HR 1.21). In multivariate analysis, overexpression of PHGDH (HR 1.19, P = 0.008), MTHFD1 (HR 1.33, P = 0.041), and ALDH1L2 (HR 1.21, P < 0.001) were independent predictors of poor survival. RFS analysis was limited by missing data; nevertheless, univariate analyses found MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 to be associated with RFS (all P < 0.05). Conclusions: Within the limits of this observational study, these data suggest that serine and one carbon metabolism is important in the progression and prognosis of muscle-invasive bladder cancer. Subsequent in vitro analyses are needed to validate the prognostic and therapeutic significance of these findings.
Characterization of human bladder cancer patient-derived xenograft in vivo and in organoids.
Authors: Lam Hung-Ming , Liu Yuzhen , Vakar-Lopez Funda , Brown Lisha , Montgomery Robert B. , Corey Eva , Hsieh Andrew Caleb , Wright Jonathan L.
Published: February 2018

479

Background: To establish and molecularly characterize a human bladder cancer patient-derived xenograft (PDX) in vivo and in an organoid system derived from the PDX for preclinical studies. Methods: Two-mm3 bits of urothelial carcinoma originated from muscle invasive disease excised in cystectomy were implanted subcutaneously into male severe combined immunodeficient mice to establish PDXs. Established PDXs (CoCaB 1) were passaged subcutaneously in SCID mice and histopathology of each passage was compared with the originating tumor. Tumor size was measured weekly by caliper to determine the growth rate of PDXs from early (P1/P2) through late passage (P8/P9). Representative early and late passages were collected for organoid establishment. For both early and late passages, proliferation was assessed by Ki67 in PDXs and organoids, and cell cycle analysis and MTS assay specifically in organoids. RNA sequencing was performed to compare the fidelity of PDX and organoids vs. primary tumor. Results: Histologically, 16 of the 16 (100%) PDXs generated from early through late passage (1-2 tumors per passage) were similar to the original high-grade urothelial carcinoma. In vivo, the latency of PDX establishment decreased upon passage (9 weeks to take in early P1/2 vs. 2 weeks to take in late P8/9) and the growth rate increased upon passage. Concordantly, Ki67 proliferation index increased from 40% in P1 to 95% in P8 and was positively correlated with increasing passage (Spearman R=0.804, p=0.001). Similarly, in organoids, late passage demonstrated a shorter growth doubling time, higher Ki67 proliferation index, and faster progression through cell cycle. Transcriptional analysis showed that the PDX contained 81-92% human transcripts, whereas organoids contained >99% human transcripts. Conclusions: Bladder cancer PDXs histologically represented the originating disease. PDX and organoid systems demonstrated concordant increase in proliferation upon serial passages, suggesting clonal selection may take place in this aggressive tumor type. Despite more mouse stromal content in PDX, PDX and organoid represent two independent model systems with highly similar biological responses that allow therapeutic studies.
Practice patterns and outcomes among patients with N0M0 prostate cancer and a very high prostate-specific antigen.
Authors: Muralidhar Vinayak , Yang David Dewei , Mahal Brandon Arvin Virgil , Rose Brent Shane , Beard Clair , Efstathiou Jason A. , King Martin T. , Martin Neil E. , Orio Peter F. , Nguyen Paul L.
Published: February 2018

48

Background: There are limited data regarding practice patterns and outcomes among patients with a very high prostate-specific antigen (PSA) level ( > = 98.0 ng/mL) but clinically localized (N0M0) prostate cancer. Methods: We used the National Cancer Database (NCDB) to identify 748,825 patients with prostate cancer diagnosed 2004-2012. We subdivided these patients by PSA level (0-9.9, 10-19.9, 20-39.9, 40-59.9, 60-79.9, 80-97.9, and > = 98.0 ng/mL), nodal status (N0 vs N1) and the presence of distant metastases (M0 vs M1). We determined the rate of definitive LR therapy (pelvic and/or prostate radiation and/or radical prostatectomy) in each group. Overall survival was compared using Cox multivariable regression modeling after adjusting for patient race, income quartile, education quartile, age, and year of diagnosis. Results: Rates of definitive LR therapy for patients with PSA > = 98.0 ng/mL and N0M0 disease were significantly lower than they were for those with N1M0 disease (52.6% vs 60.4%, p < 0.001) or with PSA < 98.0 ng/mL and N0M0 disease (52.6% vs 86.6%, p < 0.001). Among patients with N0M0 disease, 5-year OS decreased with increasing PSA: for PSA levels of 0-9.9, 10-19.9, 20-39.9, 40-59.9, 60-79.9, 80-97.9, and > = 98.0 ng/mL, 5-year OS was 91.6%, 84.3%, 80.2%, 84.1%, 81.8%, 80.2%, and 59.1%, respectively. Among those with N1M0 disease, 5-year OS was 63.2%, which in multivariable Cox regression modeling was not significantly different compared to those with PSA > = 98.0 ng/mL N0M0 disease (adjusted hazard ratio [AHR] 0.99, 95% confidence interval 0.91-1.09, p = 0.942). The survival benefit associated with LR treatment was larger among those with N0M0 high-PSA disease than among those with N1M0 disease (AHR of 0.26 vs 0.41, p-interaction < 0.001). Conclusions: Patients with clinically N0M0 disease but very high PSA ( > = 98.0 ng/mL) have similar outcomes as patients with N1 disease but receive definitive LR therapy at a lower rate. It is possible that patients with N0M0 disease and PSA > = 98.0 ng/mL represent a population that should be treated as more similar to the N1M0 population, rather than the M1 population, including consideration of LR therapy in appropriate contexts.
Effectiveness of transurethral resection (TUR) plus systemic chemotherapy as definitive treatment for muscle-invasive bladder cancer (MIBC).
Authors: Audenet François , Waingankar Nikhil , Ferket Bart , Niglio Scot Anthony , Marqueen Kathryn E. , Mehrazin Reza , Sfakianos John , Galsky Matt D.
Published: February 2018

481

Background: TUR + neoadjuvant cisplatin-based chemotherapy achieves a pathologic complete response in 30-40% of patients with MIBC. Prior studies have demonstrated that long-term survival is possible for a subset of patients with MIBC treated with TUR plus chemotherapy alone, but such analyses have been limited by small sample sizes and poor generalizability. The objective of our study was to describe the characteristics and outcomes of patients managed with this approach using a large national registry. Methods: Within the National Cancer Database (2004-2012), we identified 1,003 patients who were treated with TUR + multi-agent systemic chemotherapy, without radiation, as definitive treatment for cT2-T4aN0M0 urothelial carcinoma of the bladder. Baseline characteristics were compared relative to those of 12,138 patients treated during the same period of time with radical cystectomy ± perioperative chemotherapy. Treatment outcomes were assessed using Kaplan-Meier analysis. Results: Compared to patients who were treated with cystectomy ± perioperative chemotherapy, patients treated with TUR + chemotherapy alone were significantly older (≥75 years old 37% vs. 30%; p < 0.0001), had a higher clinical T stage (cT3: 14% vs. 12%; cT4: 12% vs 7%; p < 0.0001) and were more frequently treated in non-academic facilities (66% vs. 49%; p < 0.0001). There were no significant differences between groups regarding gender, Charlson comorbidity index, insurance type or income/education level. The 30-day and 90-day mortality with TUR + chemotherapy was 0.2% and 4%, respectively. The 5-year survival rate for all patients treated with TUR + chemotherapy was 30.5% (95% CI 26.8, 34.2), and limited to patients with cT2 disease was 33.1% (95% CI 28.7, 37.5). Conclusions: This large real-world cohort representing the continuum of practice settings in the United States confirms that long-term survival is achievable in a subset of patients treated with TUR + chemotherapy alone for MIBC. Refinement of this bladder-sparing approach integrating putative predictive biomarkers of pathologic complete response is now the focus of recently initiated prospective clinical trials.
Clinicopathological features of lipid cell variant of urothelial carcinoma.
Authors: Hayashi Tatsuro , Kimura Go , Takahashi Keigo , Shibayama Keita , Obayashi Kotaro , Sano Masayuki , Tanabe Kuniaki , Akatsuka Jun , Toyama Yuka , Hamasaki Tsutomu , Kondo Yukihiro
Published: February 2018

487

Background: Lipid cell variant (LCV) of urothelial carcinoma (UC) which was first described by Mostofi et al in 1999 is a very rare variant of UC. Because it has only been documented in occasional case reports and a small series about this variant since then, clinicopathological characteristics of LCV are not yet clarified. In this study, we assessed the clinicopathological characteristics of LCV experienced in our hospital. Methods: The medical records of patients with LCV, who were treated in our hospital between September 2015 and September 2017, were retrospectively reviewed and analyzed. Results: In this period, of 301 patients undergoing TURBT and 42 patients undergoing nephroureterectomy, 13 patients including 10 patients with bladder cancer and 3 with pelvic ureter cancer, were found to be diagnosed as LCV of UC at our hospital. The median observation period of these patients was 6 months (IQR, 4-9 months). Among 10 bladder cancer patients who had confirmed this variant in transurethral resection of bladder tumor (TURBT) specimens, all cases had concurrent high-grade UC and the most cases had tumor features including pT2 or more local stages and lympho-vascular invasion (LVI) positive. Co-existence of micropapillary and/or plasmacytoid variant were seen in 5 patients. Lymph node metastases were observed in 3 patients, and this variant was histologically confirmed within the lymph node metastatic tissue in one case. No patient had distant metastasis. Among 3 pelvic ureter cancer patients who had undergone nephroureterectomy, all cases had concurrent high-grade UC and the most cases had tumor features including pT3 local stage and LVI positive. Micropapillary variant was coexisted in one patient. No patient had distant metastasis. 7 patients were no evidence of disease and 6 were alive with disease. The estimated median time from surgery to recurrence was not reached. The 6-months disease-free survival rate was 59%. Conclusions: LCV is seen in the patients who have high-grade UC, and tends to be accompanied with other aggressive variants including micropapillary and plasmacytoid. All patients with this variant had advanced stage cancer at presentation with high recurrence rates.
Clinical outcomes of patients with histologic variants of urothelial carcinoma treated with tetra-modality bladder-sparing protocol incorporating consolidative partial cystectomy.
Authors: Kijima Toshiki , Yoshida Soichiro , Yokoyama Minato , Ishioka Junichiro , Matsuoka Yoh , Saito Kazutaka , Kihara Kazunori , Fujii Yasuhisa
Published: February 2018

490

Background: Trimodality bladder-sparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As some of the histologic variants of urothelial carcinoma (VUC) are more resistant to chemotherapy and radiotherapy compared with pure urothelial carcinoma (PUC), it is still controversial whether bladder-sparing therapy provides comparable disease control in VUC. We have developed a tetra-modality bladder-sparing therapy consisting of maximal transurethral resection (TUR), chemoradiotherapy (CRT), and consolidative partial cystectomy, which has theoretical advantage in locoregional control by surgically eliminating chemo- and radio-resistant cells (Koga et al, Urol Oncol 2013, BJU Int 2012). Methods: After maximal TUR and CRT (40Gy + cisplatin), treatment response was evaluated by cytology, imaging and tumor-site rebiopsy. Complete responders were candidate for consolidative partial cystectomy, while radical cystectomy was recommended for others. VUC identified in maximal TUR samples were categorized according to the 2004 World Health Organization Classification. Response rate to CRT, MIBC recurrence-free survival and cancer-specific survival (CSS) were compared between patients with PUC and VUC. Results: Between 1997 and 2016, 153 consecutive patients with cT2-3N0M0 bladder cancer (median age 69, female/male = 33/120, cT2/3 = 99/54) entered tetra-modality bladder-sparing protocol. VUC was identified in 37 (24%) of the patients, including glandular in 12 (8%), squamous in 11 (7%), micropapillary in 8 (5%), sarcomatoid in 2 (1%), microcystic in 2 (1%), and lymphoepithelioma-like in 1 (0.7%). There was no difference in the response rate to CRT between PUC and VUC (71% vs 84%, p = 0.13). Among the patients with PUC (n = 75) and VUC (n = 31) who underwent partial cystectomy, 5-yr MIBC recurrence-free rates were 92% and 100% (p = 0.21), and 5-yr CSS rates were 93% and 94% (p = 0.64), respectively. Conclusions: Tetra-modality bladder-sparing therapy incorporating partial cystectomy could provide favorable locoregional control and survival for patients with VUC.
Utilization and outcomes of chemoprophylaxis for the prevention of venous thromboembolism following radical cystectomy: A population-based study.
Authors: Reese Stephen , Mossanen Matthew , Zlatev Dimitar V. , Pucheril Daniel , Chung Benjamin I. , Chang Steven Lee
Published: February 2018

491

Background: Venous thromboembolism (VTE), comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major preventable source of postoperative complications. The risk of VTE in patients undergoing radical cystectomy (RC) for bladder cancer has been estimated at 6%, and the American Society of Clinical Oncology, American Urological Association, and National Comprehensive Cancer Network all recommend perioperative chemoprophylaxis. We performed a population-based analysis to determine the utilization of chemoprophylaxis against VTE in patients undergoing RC. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we retrospectively identified patients who underwent RC for bladder cancer in the US between 2006 and 2015. Administration of chemoprophylaxis within 24 hours of surgery was deemed consistent with recommendations. A subgroup analysis of higher volume hospitals (³10 RC annually) compared outcomes of DVT, PE, and bleeding between patients in hospitals with uniform use versus no use of chemoprophylaxis. Multivariate analysis was used to evaluate predictors of under-utilization of chemoprophylaxis. Results: Among the cohort of 9,133 patients (48,714 patients after weighting adjustment) undergoing RC, 35.1% were administered recommended chemoprophylaxis, with an increase in utilization from 20.7% in 2006 to 49.6% in 2015. Characteristics associated with decreased likelihood of chemoprophylaxis administration included patient age ≥65 years, Charlson Comorbidity Index score ≥2, rural hospital location, commercial insurance, and year of surgery prior to 2010. Patients who received recommended chemoprophylaxis had significantly lower rates of VTE (5.1% vs 6.0%) and PE (2.0% vs 3.1%), but elevated rates of bleeding (12.8% vs 7.7%). Conclusions: The recommended utilization of chemoprophylaxis in a contemporary nationwide cohort of patients undergoing RC is limited despite its notable increase over the course of the study period. Greater compliance with recommended use of chemoprophylaxis following RC may be associated with decreased risk of PE and VTE, but also with increased risk of bleeding.
The impact of treatment at minority-serving hospitals on outcomes for bladder cancer.
Authors: Fletcher Sean A. , Gild Philipp , Cole Alexander P , Vetterlein Malte , Kibel Adam S. , Choueiri Toni K. , Sonpavde Guru , Preston Mark A , Pucheril Daniel , Menon Mani , Sun Maxine , Lipsitz Stuart R. , Trinh Quoc-Dien
Published: February 2018

492

Background: Healthcare for racial minorities is densely concentrated at a small subset of hospitals in the United States. Understanding long-term outcomes at these minority-serving hospitals is highly relevant to elucidating the sources of racial disparities in cancer care. We investigated the impact of treatment at a minority-serving hospital on overall survival and receipt of definitive treatment for bladder cancer. Methods: Using the National Cancer Database, we identified all patients diagnosed with clinically localized, muscle-invasive bladder cancer between 2004 and 2012. Univariate and multivariable analyses were performed to assess the sociodemographic, clinical, and hospital-level factors influencing overall survival and receipt of definitive treatment (radical cystectomy with or without chemotherapy; trimodal therapy) for bladder cancer. Results: In adjusted analyses, there was no significant difference in overall survival between patients treated at minority-serving hospitals versus those treated at non-minority-serving hospitals (HR: 0.95; 95% CI: 0.90-1.01). There was also no significance in receipt of definitive treatment between the two hospital types (OR: 0.85; 95% CI: 0.68-1.06). Black race was independently associated with increased likelihood of mortality (HR: 1.08; 95% CI: 1.03-1.14) and decreased odds of receiving appropriate definitive treatment (OR: 0.73; 95% CI: 0.66-0.82). Conclusions: There was no difference between minority-serving and non-minority-serving hospitals in overall survival or receipt of definitive treatment. Black patients suffered worse survival and were less likely to receive definitive treatment for bladder cancer regardless of the type of hospital in which they were treated.
Detection and oncological impact of circulating tumor cells in bladder cancer patients with presence of copy number variations of circulating cell free DNA.
Authors: Soave Armin , Schwarzenbach Heidi , Vetterlein Malte , Rührup Jessica , Engel Oliver , Dahlem Roland , Fisch Margit , Pantel Klaus , Riethdorf Sabine , Rink Michael
Published: February 2018

495

Background: To investigate detection and oncological impact of circulating tumor cells (CTC) in bladder cancer patients with presence of copy number variations (CNV) of circulating cell-free DNA (cfDNA) treated with radical cystectomy (RC). Methods: Secondary analysis of 85 bladder cancer patients, who were prospectively enrolled and treated with RC at our institution between 2011 and 2014. Blood samples were obtained preoperatively. For CTC analysis, blood was analyzed with the CellSearch system (Janssen). cfDNA was extracted from serum using the PME DNA Extraction kit (Analytik Jena). Multiplex ligation-dependent probe amplification (MLPA) was carried out to identify CNV of cfDNA. In a single reaction MLPA allows analyzing CNV in 43 chromosomal regions containing 37 genes. Results: MLPA was suitable for characterization of CNV in 72 patients (84.7%). Data on CTC was available for 45 of these patients (62.5%). In total, 7 patients (15.6%) had CTC with a median CTC count of one (IQR: 1-3). In 21 patients (46.7%), one to 6 deleted or amplified chromosomal regions were detected with a median CNV count of 2 (IQR: 1-2). Overall, most changes were located in the genes CDH1, RIPK2 and ZFHX3 in 8 patients (17.8%), 6 patients (13.3%) and 5 patients (11.1%). Chromosomal aberrations were most frequently found on chromosome 8 in 8 patients (17.8%). Overall, presence of CTC was not associated with CNV status. However, presence of CTC was associated with copy number losses in miR-15a (p = 0.011). Patients with CTC had reduced recurrence-free survival (RFS) compared to patients without CTC (p = 0.012). In combined Kaplan-Meier analysis, patients with CTC plus presence of CNV had reduced cancer-specific survival (CSS) and RFS compared to patients without CTC but with presence of CNV (p≤0.035). In addition, patients with CTC plus presence of CNV had reduced RFS compared to patients without CTC and without presence of CNV (p = 0.028). Conclusions: CTC and CNV of various genes are detectable in peripheral blood of bladder cancer patients. The presence of CTC seems to be associated with CNV of specific genes. CTC have a negative impact on survival in patients with and without presence of CNV.
Phase II trial of BC-819 intravesical gene therapy in combination with BCG in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Halachmi Sarel , Leibovitch Ilan , Zisman Amnon , Stein Avi , Benjamin Shalva , Sidi Ami , Knickerbocker Ron , Limor Michal , Moore Yan
Published: February 2018

499

Background: BC-819 is an intravesical gene therapy consisting of a recombinant DNA construct which delivers a lethal cellular toxin, engineered from diphtheria, specifically to malignant cells in the bladder. In this study we tested the feasibility of administering BC-819 in combination with BCG with the goal of improving outcomes for patients with NMIBC. Methods: This phase II multi-center trial assessed 3 intravesical combination induction schedules of BC-819 and BCG; alternating (A), sequential (S), and twice weekly (TW) for 6-12 weeks. The population included adult patients for whom BCG was indicated. All patients underwent transurethral resection of the bladder tumor (TURBT) prior to study entry. The primary endpoint was safety; recurrence was assessed as a secondary endpoint. Results: 38 Caucasian patients were included in the intent-to-treat population; 16 in A, 6 in S, and 16 in TW cohorts. The median follow-up is 18-mo. The mean age was 69 years (±11.3), 92% were males. 29% had prior BCG. 16% of patients had CIS lesions, and 47% had multiple recurrences prior to participation. In 86% the resected tumor size ≥1.0cm. The overall median time to recurrence (mTTR) was not reached. The 24-months rates of recurrence and progression were 46% and 24%, respectively. The longest median time to recurrence among the three schedules was in the alternating group, but due to the small numbers of patients in each group the best schedule could not be determined. Therapy was associated with 5 AEs (in 5 patients; 13%) related to BC-819 (2 UTIs – 1 mild/1 moderate, 2 hematurias – both mild, 1 dysuria - mild) and 29 related to BCG. 3 SAEs were reported, none related to BC-819. Conclusions: These data demonstrate that administration of BC-819 in combination with BCG is feasible and exhibits clinically meaningful activity in all three induction schedules. The safety profile suggests that BC-819 is well tolerated and does not add substantial toxicity to intravesical therapy. A phase 3 randomized trial of BC-819 and BCG in patients with NMIBC is planned. NCT01878188. Clinical trial information: NCT01878188. [Table: see text]
Phase II trial of palbociclib (PD-0332991) in patients with metastatic urothelial cancer (UC) after failure of first-line chemotherapy.
Authors: Rose Tracy Lynn , Chism David D. , Alva Ajjai Shivaram , Deal Allison Mary , Maygarden Susan , Whang Young E. , Kardos Jordan , Drier Anthony , Kim William Y. , Milowsky Matthew I.
Published: February 2018

500

Background: UC is a common malignancy with poor outcomes in patients with metastatic disease. The majority of urothelial cancers harbor alterations in key retinoblastoma (Rb) pathway genes with CDKN2A alterations in approximately 35% of tumors, leading to loss of Rb tumor suppressor function with subsequent cell cycle progression and unchecked cell proliferation. Palbociclib is an oral, selective inhibitor of CDK4/6 that prevents Rb phosphorylation to promote cell cycle arrest. Methods: In this phase II trial, biomarker-selected (p16 loss and intact Rb by tumor immunohistochemistry [IHC]) patients with metastatic platinum-refractory UC received palbociclib 125mg po daily for 21 days of a 28-day cycle. The primary endpoint was progression-free survival at 4 months (PFS4) using a Simon’s two-stage design. Prespecified tumor analysis with next generation sequencing (NGS) including Rb pathway alterations was conducted. Results: 12 patients (67% male, median age 68 years) were enrolled. Post-platinum prognostic factors included hemoglobin < 10 g/dL, 17%; liver metastases, 0%; median time from prior therapy, 5.0 months; and Eastern Cooperative Oncology Group performance status < = 1, 92%. Overall, two of 12 patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. 58% of patients had grade ≥3 hematologic toxicity with 25% grade 3 anemia and 17% grade 3 thrombocytopenia. Using NGS, the most frequently observed somatic mutations were ARID1A, MLL2, PIK3CA, and TP53 (55% for each). No patients had CDKN2A alterations, although the majority (82%) of patients had a cell cycle pathway alteration (CDKN1A 27%, CDKN2B 27%, E2F3 18%). There was no correlation between genomic alterations and clinical outcome. Conclusions: Palbociclib demonstrated limited activity in patients with platinum-refractory metastatic UC selected for p16 loss and intact Rb by IHC. Further development of palbociclib should only be considered with improved integral biomarker selection such as NGS or in rational combination with other therapies. Clinical trial information: NCT02334527.
RX‐3117, an oral hypomethylating agent to treat advanced solid tumors: Interim results from an ongoing phase 2a study in advanced urothelial cancer (aUC).
Authors: Salgia Meghan , Pal Sumanta K. , Chung Vincent M. , Tagawa Scott T. , Picus Joel , Babiker Hani M. , Gupta Sumati , Poore Julie , Peterson Christine , Benaim Ely
Published: February 2018

501

Background: RX-3117 is an oral small molecule hypomethylating agent, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft models, including those of gemcitabine resistant bladder cancer. Preliminary data from Stage 2 of a Phase 2a clinical study of RX‐3117 as a single agent in subjects with aUC is described below. Methods: This Phase 2a study (2‐stage design, NCT02030067) evaluates the efficacy of RX‐3117 in eligible patients (aged ≥ 18 years) with refractory aUC. Primary objectives include safety and efficacy of the recommended Phase 2 dose and schedule identified in the Phase 1 portion of the study. Patients received 700 mg of oral RX‐3117 daily for either 3 weeks with 1 week off in each 4-week cycle or 4 continuous weeks. The primary endpoint is a ≥ 20% rate of progression free survival benefit (i.e., proportion of patients with stable disease for at least 4 months) and/or a 10% of evaluable patients with a partial response or better. Results: As of October 2017, 17 patients (12 males, 5 females) with aUC were treated with RX‐3117. The median age was 66 years, ECOG performance status was 0 to 1 and 53% received ≥ 3 prior therapies. Metastatic disease sites included lung, liver, lymph nodes, and mediastinum. Four patients achieved stable disease for 4 cycles of RX‐3117 treatment; one patient received treatment for 168 days and another patient for 301 days. One patient showed tumor shrinkage as measured by RECIST (‐15.5%) after 4 cycles of RX-3117; another patient showed a 19% tumor reduction after 1 cycle. The most frequent related adverse events were G1 diarrhea (13%), fatigue (13%), nausea (10%), G1/G2 anemia (10%), vomiting (10%) and G3 thrombocytopenia (10%). Conclusions: RX‐3117 is safe and well tolerable and shows preliminary evidence of anti-tumor activity. The study continues to enroll patients with aUC in Stage 2. Clinical trial information: NCT02030067.
Predictors of pathologic response after radical cystectomy for muscle invasive bladder cancer: A population-based analysis.
Authors: Pearce Shane M. , Ashrafi Akbar , Winter Matthew , Ghodoussipour Saum , Zainfeld Daniel , Gill Inderbir , Desai Mihir , Daneshmand Siamak
Published: February 2018

503

Background: Neoadjuvant chemotherapy (NAC) improves overall survival (OS) for patients with muscle invasive bladder cancer (MIBC) undergoing radical cystectomy (RC), possibly through an increase in pathologic complete response (CR), defined as a pathologic stage T0 (pT0). We sought to identify predictors of CR for MIBC. Methods: The National Cancer Database from 2004 to 2013 was used to identify patients with cT2-4cN0cM0 urothelial cell carcinoma treated with RC. Patients were grouped based on pathology as CR (pT0), partial response (PR – pTa/Tis/T1) or no response (NR - pT2 or higher). Predictors of NAC and CR were identified with multivariable logistic regression. Cox proportional hazards model was used to compare OS based on cT stage, receipt of NAC and pathologic response. Results: The study population included 10,820 patients and NAC was administered in 16.4%. Use of NAC was associated with higher cT stage (p < 0.01) and increased over time (10% from 2003-2007 vs. 24% from 2011-2013, p < 0.01). Predictors of NAC use on multivariable analysis include younger age, lower comorbidity score, treatment at an academic center, and diagnosis from 2011-2013 (p < 0.01). Overall, CR was achieved in 3.3% without NAC and 16.3% with NAC (p < 0.01). NAC improved 5-year OS for all cT stages, however the survival benefit was only observed among those achieving CR (p < 0.01). Multivariable Cox regression demonstrates that both PR (HR 0. 58, p < 0.01) and CR (OR 0.26, p < 0.01) were independently associated with improved OS among those treated with NAC. Multivariable analysis identified age (OR 0.98, p < 0.01) and increased clinical stage (cT3: OR 0.47, p < 0.01; cT4 OR 0.54, p < 0.01) as negative predictors of CR. Utilization of NAC (OR 4.82 p < 0.01), academic institution, and diagnosis 2011-2013 (OR 1.92, p < 0.01) increased the odds of CR. Conclusions: Use of NAC increased over time and CR occurred in 16% of patients who received NAC. Treatment at an academic center, diagnosis from 2011-2013 and use of NAC were independently associated with CR, while increased age and clinical stage were negative predictors of CR. PR and CR are independently associated with improved OS relative to non-responders.
A decision-support tool to assist muscle-invasive bladder cancer patients choosing between radical cystectomy and chemoradiotherapy.
Authors: Baumann Brian Christopher , Hwang Wei-Ting , Srinivasan Sharadha , Wang Xingmei , Mamtani Ronac , Vaughn David J. , Xia Leilei , Malkowicz S. Bruce , Guzzo Thomas J. , Christodouleas John Paul
Published: February 2018

505

Background: Patients with high-risk muscle-invasive bladder cancer (MIBC) who are borderline medically operable for radical cystectomy (RC) face a difficult decision between RC which has higher short-term treatment-related morbidity/mortality & chemoradiotherapy (CRT) which is better tolerated in the short-term but may have worse long-term cancer control outcomes. There are no existing decision support tools to assist patients & providers in understanding these trade-offs. Herein, we developed a visualization tool to inform patients & providers how the relative risks & benefits of RC & CRT vary over time with respect to overall survival (OS). Methods: We identified cT2-3 N0 M0 urothelial bladder cancer patients ≥65 y/o treated with RC +/- chemo (n = 5981) or definitive-dose CRT after TURBT (n = 793) in the National Cancer Database, 2003-2011. The database was split into a development & validation cohort. Multivariate Cox regression with time-varying hazard ratio was performed to assess pre-treatment factors associated with OS. The inverse probability of treatment weighting method using the propensity score was employed to reduce selection bias. External validation was performed. Visualization tool showing adjusted survival curves based on pre-op patient features was generated with input from patients & a multidisciplinary expert panel. Tool calculates median OS & the “break-even point,” where the short-term OS disadvantage of RC equals the long-term advantage of RC (i.e. the point where the restricted mean survival for RC & CRT are equal). Results: On MVA, significant predictors of OS were age, Charlson Deyo comorbidity index, & cT stage (p < 0.001 for all). Using these results, we iteratively developed a web application that utilizes clinical inputs to generate patient-specific survival curves that display estimated OS differences over time. Median OS, the break-even point, & percent alive at the break-even point are provided. Conclusions: This is the first decision-support tool developed to assist high-risk borderline operable MIBC patients & their providers in understanding the short-term & long-term trade-offs between RC & CRT. Additional testing is underway.
Long-term follow-up of clinical presentation and outcomes of patients with urinary bladder paragangliomas.
Authors: Rayn Kareem , Weintraub Michael Daniel , Pena-LaGrave Gustavo , Gold Samuel , Hale Graham R. , Bloom Jonathan , Brancato Sam Joseph , Agarwal Piyush K.
Published: February 2018

507

Background: Urinary bladder paragangliomas (UBPGLs) are extremely rare, accounting for less than 6% of paragangliomas (PGLs) and 0.06% of bladder tumors. The goal of this study is to examine the presentation, clinical characteristics and outcomes of patients with UBPGLs. Methods: We determined the presenting symptoms, clinical characteristics, and outcomes of patients who presented to a single institution with UBPGLs from 2000-2017. Results: 28 patients with an average age of 27 ± 15.6 at symptom onset presented to the NIH from 2000-2017. The majority had standard paraganglioma symptoms (n = 24, 85.7%) defined as headaches, palpitations, pallor and anxiety, and hypertension (n = 20, 71.4%) on presentation. 8 patients (29%) presented with hematuria; hematuria was the only presenting symptom in 1 of these patients. 3 (10.7%) of the patients were completely asymptomatic and were discovered to have bladder paragangliomas incidentally on imaging. Overall, 9 patients (32%) were under 18 (average age = 10.9 ± 3.9) at symptom onset. 14 (50%) patients developed metastasis, with bone (n = 9) and lung (n = 8) being the most common metastatic sites. All but 1 patient received surgical treatment, with 6 patients receiving transurethral resection of bladder tumor (TURBT), 3 receiving robotic-assisted partial cystectomy (RAPC) and the remaining patients undergoing open cystectomy. In total, 2 patients experienced bladder cancer recurrence, both of whom had undergone TURBT. Comparing patients with and without hematuria, metastasis and standard paraganglioma symptoms, we found no statistically significant difference in mean diameter of the largest lesion or plasma catecholamine values. Conclusions: Our experience reveals that most patients with UBPGLs present at an early age with characteristic paraganglioma symptoms. Despite the variety of surgical methods used to manage these patients, the only 2 recurrences were in patients who underwent TURBT. Further work is necessary to establish preoperative indicators of disease severity in patients with UBPGLs. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program
Characterization of urinary bladder paragangliomas in patients with germline mutations.
Authors: Rayn Kareem , Weintraub Michael Daniel , Pena-La Grave Gustavo R , Hale Graham R. , Gold Samuel , Bloom Jonathan , Brancato Sam Joseph , Agarwal Piyush K.
Published: February 2018

508

Background: Data on the genetic characteristics of patients with urinary bladder paragangliomas (UBPGLs) is extremely limited. The primary goal of this study is to examine the clinical characteristics of a series of patients with UBPGLs, focusing particularly on their genetic profiles. Methods: We analyzed the medical records of patients who presented with UBPGLs from 2000 to 2017 to determine their presenting symptoms, clinical characteristics and outcomes. In addition, patients were stratified by the presence or absence of metastasis and the presence or absence of multiple paragangliomas (PGLs). Groups were compared using chi-square test and t-test (Stata) statistical analyses. Results: 18 of the 28 patients (64.2%) with UBPGLs had underlying genetic mutations: 15 (53.5%) in the succinate dehydrogenase subunit B gene (SDHB) and 3 (10.7%) in the von Hippel-Lindau gene (VHL). The average age at first symptoms was significantly younger in patients with germline mutations compared to those without mutations (22.3 ± 2.52 vs 37.3 ± 5.95, p = 0.01). 7 patients (38.9%) with germline mutations developed metastasis, at either first presentation or on follow-up, compared to 7 patients (70%) without germline mutations, p = 0.15. 10 patients (58.8%) with germline mutations had multiple PGLs compared to 1 patient (11.1%) without germline mutations, p = 0.02. On average, patients with germline mutations had larger lesions than patients without germline mutations based on the means of the largest diameter (3.7 ± 2.6 vs 3.1 ± 2.2, p = 0.51). Conclusions: Patients presenting with UBPGLs should be screened for underlying germline mutations as they are frequently associated. Patients with UBPGLs and underlying germline mutations present at a significantly younger age than patients without these mutations. Even though patients with UBPGLs and underlying mutations are significantly more likely to develop multiple PGLs, the risk of metastasis is not greater compared to patients without germline mutations. Therefore, all patients with UBPGLs should be followed closely for metastatic development. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program.
Phase Ib trial of ALT-803, an IL-15 superagonist, plus BCG for the treatment of BCG-naïve patients with non-muscle-invasive bladder cancer.
Authors: Rosser Charles Joel , Nix Jeffrey , Ferguson Lydia , Hernandez Liza , Wong Hing C.
Published: February 2018

510

Background: The current standard of care for patients with high risk NMIBC is a TURBT or biopsy followed by a 6-week induction course of intravesical BCG and supplementary maintenance therapies every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG, 50% of patients are still expected to recur within 12 months ( Sfakianos 2014). The pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This phase Ib clinical trial evaluates the safety and tolerability of ALT-803, an IL-15 superagonist, plus BCG in BCG-naïve NMIBC patients. Methods: A dose escalation 3+3 design was employed to evaluate intravesical ALT-803 plus 50 mg BCG in BCG-naïve patients with intermediate or high-risk Ta, T1 or Tis stage NMIBC. Patients received intravesical ALT-803 in conjunction with BCG weekly for 6 consecutive weeks (induction) and then encouraged (but not required) to receive maintenance BCG alone as per standard practices. Patients had a routine cystoscopy and voided urinary cytology (VUC) every 3 months for 2 years to determine response. Negative cystoscopy, VUC and/or biopsy yielded a complete response (CR). No cohort (100, 200 or 400 μg/instillation ALT-803) experienced any dose limiting toxicities. Results: All patients are disease-free (CR) at 24 months; no patients experienced disease recurrence or progression. Adverse events consistent with SoC BCG treatment (hematuria and urinary tract pain) were reported in all cohorts. One patient experienced a grade 3 adverse event of hypertension that resolved the same day. No grade 4 toxicities or DLTs were observed. Clinical trial information: NCT02138734. Conclusions: Intravesical ALT-803 plus BCG treatment is well tolerated in BCG-naïve patients with NMIBC. All patients are disease-free 24 months after treatment with BCG and ALT-803. A randomized phase II trial is currently underway.[Table: see text]
Between-surgeon variation in 90-day mortality after radical cystectomy for bladder cancer.
Authors: Rudzinski Jan Krzysztof , Jacobsen Niels , Ghosh Sunita , Fairey Adrian S
Published: February 2018

512

Background: Radical cystectomy for bladder cancer is a complex surgical oncology procedure. Given the high degree of skill required to perform radical cystectomy, it is plausible that outcomes may vary among surgeons. We determined whether between-surgeon variation, known as heterogeneity, exists for urologic surgeons practicing at a Canadian academic center. Methods: A retrospective analysis of data from the University of Alberta (UA) Radical Cystectomy Database was performed. Between September 1994 and August 2017, 1031 consecutive patients underwent curative-intent radical cystectomy for histologically proven urothelial carcinoma of the bladder (cTanyN1-3M0) by 1 of 11 urologic surgeons. The main outcome measure was 90-day mortality rate. Multivariable models were used to evaluate heterogeneity in 90-day mortality rate after adjustment for case mix. Statistical tests were two-sided (p≤0.05). Results: Data were evaluable for 1031 patients. There was between-surgeon variation in the 90-day mortality rate (unadjusted range, 0.9% to 13.1%). 3 surgeons had 90-day mortality rates ≤ 3% whereas 5 surgeons had 90-day mortality rates ≥ 5%. Conclusions: A patient’s likelihood of achieving an optimal perioperative outcome differs depending on which urologic surgeon performs his/her radical cystectomy. Research examining the mechanism (s) underlying surgical heterogeneity in perioperative outcome after radical cystectomy is needed.