bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.