bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world (RW) evidence of vinflunine in metastatic urothelial cancer (mUC): A systematic review of seven European studies.
Authors: Passalacqua Rodolfo , Medioni Jacques , Castellano Daniel E. , Ullén Anders , Bamias Aristotelis , Hussain Syed , Hegele Axel 
Published: February 2018

463 Background: Vinflunine is the only chemotherapy agent for which there is a marketing authorisation in Europe for platinum-pretreated patients (pts) with mUC, based on a randomized phase III clinical trial. However, RW data regarding long-term efficacy and safety of vinflunine in unselected populations is needed. We conducted a systematic review gathering RW data from published observational European studies. Methods: Controlled studies and case series were excluded. We systematically explored the following endpoints: Overall Response Rate (ORR), Progression-Free Survival (PFS), Overall Survival (OS) and toxicity. Results: From 2014 to 2017, seven post-marketing studies including 750 pts were published: one was prospective and six were retrospective. Median ORR and median OS ranged from 13% to 29% and 6.3 to 11.9 months (mo) respectively (see Table below). In long-term survivors, OS reached 20.5 mo. Initial doses ranged from 250 to 320 mg/m2 adapted to patient’s conditions. In multivariate analysis, OS was found to be associated with the following risk-factors at baseline: ECOG PS >0, hemoglobin <10 g/dl, and presence of liver metastasis. The favorable safety profile demonstrated in randomized trials was confirmed. Main toxicity was hematological: neutropenia (G 3/4 in 1% to 23%) and anemia (G 3/4 in 4% to 33%). Constipation seemed to be less frequent than previously reported (G 3/4 in 5% to 22%). Conclusions: This is the largest experience of vinflunine use in platinum-pretreated pts with mUC. In our RW evidence, vinflunine shows both efficacy and a safe profile in an unselected patient population with similar criteria as in the pivotal trial. These findings reinforce the role of vinflunine in mUC, particularly if compared to evidence with taxanes or the increasing costs of immunotherapy.[Table: see text]
Real-world survival and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma treated with second-line therapy after platinum-based chemotherapy.
Authors: Simeone Jason C , Nordstrom Beth L , Patel Ketan , Klein Alyssa B , Horne Laura 
Published: February 2018

466 Background: Median overall survival for patients with locally advanced/metastatic urothelial carcinoma (UC) who fail standard platinum-containing chemotherapy is 5–7 months, and there is no current standard of care for these patients. As immuno-oncology (IO) therapies are being developed for the treatment of UC, including some recent approvals, a better understanding of the current real-world treatment patterns and effectiveness of treatments is needed. Methods: Patients with locally advanced/metastatic UC receiving second-line therapy after platinum-based chemotherapy were identified from the Flatiron Oncology electronic medical record database from 2011–2016. Treatment patterns, including the most common regimens and total number of systemic therapy treatment lines, were characterized. Median overall survival (OS) and associated 95% confidence intervals (CI) were calculated from the start of second-line therapy using Kaplan-Meier curves. Results: A total of 476 patients met all study criteria; mean age was 70.1 ± 9.2 years and 74.2% were male; <3% were tested for PD-L1 during follow-up. Platinum-based chemotherapies were most commonly prescribed (Table 1), 4.4% received IO during second-line. Median OS from start of second-line therapy was 8.3 months (95% CI: 7.2–8.9). Conclusions: Real-world OS among locally advanced/metastatic UC patients who received second-line therapy after platinum-based chemotherapy was less than one year, similar to prior estimates. It remains to be seen how the introduction and increasing uptake of IO may affect OS. [Table: see text]
The Bristol Bladder trial: A single-arm phase II trial of cisplatin and cabazitaxel for muscle invasive transitional cell carcinoma of the urinary bladder prior to radical cystectomy.
Authors: Bahl Amit , Masson Susan , Challapalli Amarnath , Bravo Alicia , Pearson Sylvia , Hilman Serena , Persad Raj , Koupparis Anthony , Rowe Edward , Foulstone Emily , Evans Heidi , Oxley Jon , Greenwood Rosemary , Kirk Hannah , Huckett Rebecca , Kabala Julian , Ash-Miles Janice , Dailami Narges , Perks Claire , Holly Jeff 
Published: February 2018

468 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle invasive transitional cell carcinoma (MI-TCC). However response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel (CBZ) with cisplatin (CIS) in this setting. Methods: A single arm phase 2 study was designed with 80% power to detect an objective response rate (ORR) of >35%. Patients with MI-TCC were included if fit to receive neoadjuvant chemotherapy and to undergo radical cystectomy. Treatment was with CIS 70mg/m2 and CBZ 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Primary prophylaxis was with pegylated GCSF. Toxicity was recorded using CTCAE v.4.03. Objective response was defined as a reduction in Tumour (T) stage from T2 or greater at diagnosis, to T1 or less at radical cystectomy. QoL data was assessed during and after chemotherapy using EQ-5D and EORTC-BLM30 questionnaires. Results: 28 patients were enrolled with median age 68.6 years (range 47-79). Response outcome (first 23 cases) and toxicity data (first 24 cases) are in this abstract; the remaining cases, currently scheduled for surgery, will be added to the final presentation. Pathological complete response (pCR) was observed in 7/23 patients (30.4%) and ORR was 56.5% (13/23). 18/24 (75%) completed 4 cycles; reasons for stopping were disease progression (2/24, 8.3%), adverse events (2/24, 8.3%) and patient choice (2/24, 8.3%). 7/24 patients (29%) experienced treatment related grade 3 and 4 adverse events. Conclusions: These results demonstrate that CIS and CBZ chemotherapy has an acceptable safety profile and is well tolerated in this setting. This combination shows promising efficacy (pCR 30.4%, ORR 56.5%) prior to definitive treatment for MI-TCC. Response outcomes for all patients and QoL data will be reported in the final presentation. Grade 3/4 adverse events. Clinical trial information: NCT01616875. [Table: see text]
Next generation sequencing of urothelial bladder cancer: Memorial Sloan Kettering Cancer Center experience in 454 patients.
Authors: Isharwal Sumit , Audenet Francois , Drill Esther N. , Ostrovnaya Irina , Pietzak Eugene J. , Al-Ahmadie Hikmat , Cha Eugene K. , Donahue Timothy F. , Teo Min Yuen , Funt Samuel , Arcila Maria E. , Berger Michael F. , Rosenberg Jonathan E. , Bajorin Dean F. , Coleman Jonathan , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Iyer Gopa 
Published: February 2018

469 Background: Genomic characterization of urothelial bladder cancer (UBC) may help to identify alterations associated with tumor stage, novel therapeutic targets and biomarkers to predict outcomes. Methods: 454 UBC patients were sequenced using next generation sequencing assay (MSK−IMPACT). 264 patients (123 NMIBC, 112 MIBC and 29 metastatic) were chemotherapy naïve primary tumors. Results: Patients whose primary tumors harbored TP53, RB1, TP53/MDM2, and cell cycle pathway alterations more frequently presented with advanced disease whereas those with tumors containing FGFR3, and RTK/RAS/RAF pathway alterations generally presented with NMIBC (all FDR < 0.001). TP53, RB1, TP53/MDM2, and cell cycle pathway alterations were associated with worse overall and metastasis free survival whereas FGFR3 alterations were associated with more favorable overall and metastasis free survival (all FDR < 0.05). RTK/RAS/RAF pathway alterations were associated with more favorable metastasis free survival (FDR = 0.01). MIBC with no DDR alterations, DDR alterations of unknown significance and DDR deleterious alterations had pathologic downstaging rates of 37%, 48% and 81% with platinum-based neoadjuvant chemotherapy (p = 0.013). Patients with ERCC2 mutations had significantly higher pathologic downstaging with platinum-based neoadjuvant chemotherapy compared to patients without ERCC2 mutations (p = 0.025). MIBC with DDR alterations had better overall survival with neoadjuvant chemotherapy compared to MIBC without DDR alterations (p = 0.04). Of note, MIBC cases with and without DDR alterations have similar overall survival in the absence of neoadjuvant chemotherapy (p = 0.78). Conclusions: TP53, RB1 and FGFR3 alterations as well as TP53/MDM2, cell cycle and RTK/RAS/RAF pathway alterations showed an association with tumor stage and patient outcomes. MIBC with DDR alterations had higher pathological downstaging as well as better overall survival compared to MIBC without DDR alterations with platinum−based neoadjuvant chemotherapy. In absence of neoadjuvant chemotherapy, MIBC with and without DDR alterations have similar patient outcomes.
Utility of lymph node dissection for clinical node negative upper tract urothelial cell carcinoma: A multicenter study.
Authors: Hamilton Zachary , Haifler Miki , Krabbe Laura-Maria , Clinton Timothy N , Han Daniel , Ryan Stephen , Reddy Madhumitha , Field Charles , Bloch Aaron , Wan Fang , Uzzo Robert , Margulis Vitaly , Derweesh Ithaar 
Published: February 2018

474 Background: Upper tract urothelial cell carcinoma (UTUC) is an uncommon malignancy with disparate outcomes. Although use of lymph node dissection (LND) for urothelial cell carcinoma of the bladder has survival benefit even in setting of negative nodal status, therapeutic benefit of LND in the setting of clinical node negative disease for UTUC is unclear. We evaluated survival outcomes for UTUC after LND. Methods: Multicenter retrospective analysis of UTUC patients undergoing nephroureterectomy (NU) for clinical node negative, non-metastatic disease from 2001-2016 (cTis/1-T3N0M0). The cohort was divided based on pathologic lymph node status (pNx, pN0, and pN+). Primary outcome was overall survival (OS). Secondary outcome was recurrence free survival (RFS). Cox regression (CR), logistic regression (LR) and Kaplan−Meier (KMA) analyses were utilized. Results: 191 patients were analyzed (mean age 71.1 years, mean follow up 30.4 months, 27% ureteral location). LND was performed in 40.8% (78) and pN+ was noted in 11.0% (21). Mean number of nodes removed for pN0 = 6.6 and pN+ = 3.9 (p = 0.22). On CR for worsened all-cause mortality, significance was noted for ≥pT2 (OR 1.9, p = 0.031), recurrence (OR 2.3, p = 0.003), and pN+ (OR 2.8, p = 0.004). On KMA, 5 year OS stratified by pathologic node status and nuclear grade (grade 1-2 = LG; grade 3-4 = HG) noted negative survival effect associated with pN+ and HG disease (pN0 LG 85.7%, pN0 HG 41.2%, pNx LG 58.1%, pNx HG 51.1%, pN+ HG 10.7%, log-rank p < 0.001). No patient with pN+ had LG disease. On LR HG disease was predicted only by increasing clinical tumor size (OR 1.3, p = 0.032). No significant difference in complications was noted between the groups (p = 0.1). Conclusions: In clinical node negative disease, LND for UTUC did not have survival benefit; however, LND for UTUC provided prognostic information without significantly increasing risk of complications. Finding of pN+ disease was associated with worsened prognosis. LND may be omitted in LG disease yet should be considered in patients with HG disease and increasing tumor size. Further investigation is requisite.
Bladder cancer rapid autopsy: A mechanism for collecting metastatic tumor tissue and establishing xenograft models of metastatic disease.
Authors: Lam Hung-Ming , Vakar-Lopez Funda , Hsieh Andrew Caleb , Corey Eva , Montgomery Robert B. , Wright Jonathan L. 
Published: February 2018

478 Background: Patients with metastatic bladder cancer have a poor prognosis with a median survival of only 9-15 months. Understanding the biology of metastatic bladder cancer has been historically difficult due to a paucity of specimens and models that recapitulate human disease. We established a bladder cancer rapid autopsy program to systemically acquire metastases, and build patient-derived xenograft (PDX) and organoid models for biological studies. Methods: Patients with metastatic bladder cancer were consented and a rapid autopsy was performed 2-6 hours after death to allow acquisition of normal and metastasis specimens. Frozen and formalin-fixed and paraffin embedded specimens were collected and pathological evaluation was performed on each specimen. Additionally, tumors were implanted subcutaneously into SCID mice to establish PDXs. Once PDXs were developed, PDXs were dissociated for companion organoid culture. Clinical history and treatment information was documented for each patient. Results: We have performed 10 bladder cancer rapid autopsies to date, and have acquired 105 metastatic and 45 normal specimens. The pathological subtypes of patients include urothelial cell carcinoma (5/10), squamous cell carcinoma (3/10), and plasmacytoid variant of urothelial carcinoma (2/10). The cohort has been treated BCG only (1/10), chemotherapy (3/10), and chemotherapy and immune checkpoint inhibitors (6/10). The leading site of metastasis was the liver (7/10) and lung (7/10), followed by lymph node (5/10), bone (5/10), intestine (4/10), and omentum (2/10). Half (5/10) of the patients had extensive liver metastases that allow acquisition of multiple tumor foci. For the first time, PDX and organoids from two independent metastases (omentum – CoCaB 14.1 and liver –CoCaB 14.2) from the same patient were successfully developed. Conclusions: This bladder cancer rapid autopsy program provides an important volume of metastatic tumor specimens for study. Importantly, the first bladder cancer PDX derived from metastasis has been developed. The availability of metastatic bladder cancer specimens, PDXs, and organoids will allow biological studies of advanced disease.
Plasmacytoid urothelial carcinoma: A clinicopathological study.
Authors: Hashemi-Sadraei Neda , Perrino Carmen M , Monn M. Francesca , Bandali Elhaam , Cheng Liang , Idrees Muhammad , Bihrle Richard , Koch Michael O. , Eble John , Kao Chia-Sui , Albany Costantine , Pili Roberto , Grignon David A. , Kaimakliotis Hristos Z. 
Published: February 2018

482 Background: Plasmacytoid urothelial carcinoma (PUC) is a rare variant histology with poor prognosis. We report clinical outcomes on patients with PUC. Methods: We retrospectively reviewed treatments and outcomes in patients with PUC seen at our institution from 1996 through 2016. The Kaplan-Meier method was used to calculate overall survival. Results: A total of 69 patients with a median age of 68 years were identified. Five patients presented with metastatic disease, whereas 64 were diagnosed with clinically localized PUC. Fifty-seven patients underwent radical cystectomy and the remainder elected for bladder preservation approaches. At time of cystectomy, 6 patients were found to have pathologically organ-confined disease (≤pT2 N0), and 51 had non-organ-confined disease (pT3,T4 or N+), 2 of which were noted to have diffuse peritoneal carcinomatosis. Twenty-eight patients had positive surgical margins, most of which had extensive infiltrative disease not amenable to complete excision. Of the 14 patients who received neoadjuvant cisplatin-based chemotherapy, 10 (71.4%) patients had lymph node involvement and 12 (85.7%) had pT3/4 disease at cystectomy. Only one patient had a pathologic complete response with pT0N0. Thirteen patients received adjuvant chemotherapy, 2 of which received neoadjuvant chemotherapy as well. Two patients received immunotherapy, with only a short-lived response. Median survival for all patients with PUC from time of initial diagnosis was 17.7 months (mo), and 14.0 mo from time of cystectomy for patients undergoing radical cystectomy. Patients with desmoplastic morphology tended to have the worst clinical outcomes (median survival 10.1 mo), whereas classic and pleomorphic subtypes had better survival (median survival 18.6 and 30.4 mo, respectively) (p = 0.083). Conclusions: PUC is an aggressive variant with overall poor outcomes. There appeared to be three morphologic subtypes of plasmacytoid disease; classic, desmoplastic and pleomorphic, with potentially distinct survival outcomes. Chemotherapy, whether in the neoadjuvant or adjuvant setting, or immunotherapy, appeared to have little effect on this cohort. Molecular markers/genomic analysis may provide insight to novel therapeutic approaches.
Significance of serum buttyrylcholinesterase level before chemotherapy as an independent predictor of overall survival in patients with metastatic upper-tract urothelial cancer.
Authors: Yoneyama Takahiro , Kodama Hirotake , Hosogoe Shogo , Kusaka Ayumu , Tokui Noriko , Yoneyama Tohru , Imai Atsushi , Yamamoto Hayato , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2018

486 Background: Systemic inflammation is a common host reaction to cancer progression. Serum level of buttyrylcholinesterase (BChE) have been reported to reflect the presence of inflammation and other clinical conditions. BChE is an alphaglycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, injury, infection, and malignant disease. We retrospectively evaluated the potential prognostic significance of buttyrylcholinesterase before chemotherapy as an independent predictor of overall survival in patients with advanced upper-tract urothelial cancer. Methods: We treated seventy-four patients (52 men and 22 women) with advanced upper-tract urothelial cancer (UTUC) at our clinic between August 2004 and September 2017. The average age was 69.3 (43–89), and average eGFR was 50.5 (11.6–99.3) ml/minute/1.73m2. Mean observation period was 28.7 (3–111) months. Levels of serum BChE (normal range 168-470 U/L) were measured 1 week before chemotherapy. The average serum level of BChE were 240.6 U/L (53-509). The patients received 2 courses of GCarbo consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. If this regimen was effective, another 2 courses of GCcarbo was performed. If this regimen did not induce any tumor size reduction, we switched to 2 courses of GCarboD (D; 70mg/m2) treatment as second-line treatment. Results: GCarbo regimen yielded 5 cases (6.8%) of CR, 32 (43.2%) of PR, and the average duration of response of 11.4 (2–29) months. GCarboD treatment was administered in 21 cases, and yielded 2 (9.5%) PR and a duration of response was 31.5(7-50) months. The median over-all survival period was 14.3 months. When analyzed by serum BChE level, the ovearall survival were 22.0 months in the BChE > 168 U/L group and 11.0 months in the BChE < 168 group (p = 0.0035). The level of serum BChE showed no association with treatment effect. Conclusions: Serum BChE level before chemotherapy may have the potential to predict overall survival in patients with advanced upper-tract urothelial cancer.
Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression.
Authors: Joerger Markus , Cassier Philippe , Penel Nicolas , Cathomas Richard , Richly Heike , Schostak Martin , Janitzky Andreas , Wermke Martin , Nogova Lucia , Tai David Wai-Meng , Sayehli Cyrus , Grüllich Carsten , Grande Enrique , Navarro Alejandra , Park Se Hoon , Gillessen Silke , Nogai Hendrik , Bender Sebastian , Ellinghaus Peter , Schuler Martin H. 
Published: February 2018

494 Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the results from a phase I expansion cohort in UC patients prescreened for FGFR1-3 mRNA expression levels and activating mutations. (NCT01976741) Methods: Patients with advanced urothelial carcinomas were selected based on high FGFR1-3 mRNA expression in biopsy specimens. Selected patients were treated with rogaratinib 800mg twice daily until tumour progression, untolerable toxicity, or withdrawal. Tumor response was assessed by RECIST, v1.1. Adverse events were reported using CTCAE v4.03 criteria. Results: A total of 219 UC patients were prescreened for FGFR1-3 mRNA expression levels and FGFR3 activating mutations, with 99 samples (45%) found to be FGFR-positive. Of those, 87% of samples were positive for FGFR3 mRNA, 5% for FGFR1 mRNA and 8% were double FGFR mRNA-positive (FGFR1/2, 1/3 or 2/3). Frequency of FGFR3 activating mutations in UC samples was 7%, all of which also had high FGFR3 mRNA. Fifty two patients (median prior line of treatment 2) started treatment and 51 were evaluable for response. Rogaratinib was generally well tolerated and AEs manageable with dose modification. The most common AEs were diarrhea (49%) and hyperphosphatemia (49%). Objective response rate (ORR) was 24% (12/51; all PRs) and disease control rate (DCR) was 73% (37/51). Eleven of 12 pts with a PR were positive for FGFR3 mRNA, 5 of whom also had FGFR3 mutations, and one patient was positive for FGFR1 mRNA. Ten FGFR-positive UC patients had prior immuno-oncology (I/O) treatment, 9 of whom had progressive disease as best response. For these 10 patients the ORR was 30% and the DCR 80%. Conclusions: Selection of pts for treatment with rogaratinib based on FGFR mRNA expression levels was feasible and identified drug-sensitive patients with and without underlying DNA alterations. Rogaratinib had a favorable safety profile and showed promising anti-tumor activity in UC patients. Responses and disease stabilization were observed with rogoratinib in UC pts refractory to prior I/O treatment. Clinical trial information: NCT01976741.