bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk group stratification in patients with micropapillary bladder cancer treated with radical cystectomy and/or neoadjuvant chemotherapy.
Authors: Williams Stephen Bentley , Fernandez Mario , Willis Daniel Levi , Slack Rebecca , Siefker-Radtke Arlene O. , Navai Neema , Dickstein Rian J. , Guo Charles , Czerniak Bogdan , McConkey David James , Parikh Sahil , Pisters Louis L. , Shah Jay Bakul , Grossman H. Barton , Dinney Colin P. N. , Kamat Ashish M. 
Published: February 2017

302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carcinoma. We have previously published clinical risk stratification groups for patients with conventional urothelial carcinoma and sought to identify if these were valid in patients with this variant histology. Methods: An IRB approved review of 1910 patients in our radical cystectomy database revealed 106 patients with preoperative diagnosis of ≤cT4aN0M0 MPBC between December 1992 and January 2012 who underwent upfront radical cystectomy (RC, n = 74) or neoadjuvant chemotherapy (NAC) followed by RC (n = 32). To determine whether patients with MPBC can be risk stratified using traditional risk factors, a recursive partitioning analysis (RPA) was performed. Results: In multivariate analyses, hydronephrosis (HR=3.1; p=0.01), and extent of MPBC at transurethral resection (TUR) (HR=1.9; p=0.04) were associated with shortened OS. In the reduced model, clinical stage also achieved significance (HR=2.8; p=0.03). Results were similar for DSS: hydronephrosis (HR=2.4, p=0.03), extent of MPBC (HR=2.1, p=0.03) and clinical stage (HR=4.7, p=0.02). Using the RPA analysis, following risk groups were identified according to OS or DSS: 1) cT1 disease with no hydronephrosis; 2) cT2 or higher with no hydronephrosis; or 3) hydronephrosis (with any cT stage). These groups corresponded to a low, intermediate and high-risk groups with 5-year OS and DSS rates of 85% and 91%, 50% and 57% and 16% and 17%, (p<0.001), respectively. We found these risk groups to hold true in those treated with NAC or upfront RC; those who received NAC trended towards better outcomes. Conclusions: In patients with MPBC, preoperative risk factors can help stratify patients into different risk groups similar to what is seen in patients with conventional UC. Presence of hydronephrosis is an especially ominous sign.
Safety and efficacy of temsirolimus as second-line treatment for patients with recurrent bladder cancer.
Authors: Houede Nadine , Roubaud Guilhem , Mahammedi Hakim , Vedrine Lionel , Joly Florence , Mourey Loic , Pfister Christian , Culine Stephane , Goberna Alejandro , Lortal Barbara , Pulido Marina , Pourquier Philippe , Bellera Carine A. 
Published: February 2017

304 Background: Bladder cancer is the 7th cause of death from cancer in men and 10th in women. For metastatic patients, prognosis is poor with a median overall survival of 15 months that remained unchanged for the past 15 years. No standard second-line chemotherapy is available for patients who relapse. Acquired mutations leading to a deregulation of the PI3K/AKT/mTOR pathway have been reported in more than 40% of bladder cancers suggesting the use of the mTOR (mammalian target of rapamycin) signalling pathway as an attractive target for the treatment of urothelial tumors. Methods: The main objective of this study was to assess the efficacy of temsirolimus, an mTOR inhibitor that is already used for the treatment of renal cancers, in patients with recurrent or metastatic bladder cancer who already received a first line chemotherapy. Efficacy was measured in terms of non-progression of the disease at two months of treatment following the RECIST v1.1 criteria. Based on a two-stage optimal Simon’s design, a total of 15 non-progressions out of 51 eligible and assessable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg until progression, unacceptable toxicities or withdrawal. Results: Fifty-four patients were enrolled in the study between November 2009 and July 2014 in seven French centres. At the end of the first stage, six patients out of 17 were progression-free at 2 months leading to the inclusion of additional 37 patients in the second stage of the study. Thirty-six patients were eligible and assessable for the primary efficacy endpoint. A total of 18 (50%) non-progressions were observed at 2 months. Among them, partial response was documented for two patients and stable disease for 16. Twenty-five related adverse events were observed in 19 (35.2%) of the patients. Conclusions: Our study is providing the first clinical evidence of a potential benefit of temsirolimus for the treatment of relapsed bladder cancers. Ancillary study is ongoing to investigate the mutational status of genes which are involved in the PI3K/AKT/mTOR signalling pathway in order to identify a predictive signature of response to temsirolimus in bladder cancer. Clinical trial information: NCT0187943NCT0187943.
Second-line chemotherapy for metastatic urothelial cell carcinoma: Pooled analysis and construction of a prognostic model.
Authors: Salah Samer , Lee Jae-Lyun , Rozzi Antonio , Kitamura Hiroshi , Matsumoto Kazumasa , Srinivas Sandy , Morales Rafael , Carles Joan , Al-Wardat Rami , Maakoseh Mohammad 
Published: February 2017

309 Background: A prognostic model for patients with metastatic urothelial cell carcinoma (UCC) progressing following platinum-based therapy was constructed based on data from the phase 3 vinflunine trial. However, prognostic information for patients treated outside the setting of clinical trials and with variety of second-line regimens are limited. Methods: We gathered individual patient’s data from studies assessing second-line chemotherapy for metastatic UCC and analyzed the influence of factors of interest on overall survival (OS) through univariate and multivariate Cox-regression analysis. A prognostic model was constructed, and data of an independent series from a single institution was utilized for validation. Results: Data for 182 patients from seven studies were pooled. The second-line treatment was single agent in 22 (12%), platinum-based combination (nedaplatin or oxaliplatin) in 59 (33%), and non-platinum combination in 101 (55%). In multivariate analysis, Eastern Cooperative Oncology Group performance status ≥1, Hb<10, and metastatic patterns other than LN only metastasis emerged as independent adverse factors. Patients with all three factors (poor risk), 1-2 factors (intermediate risk), and 0 factors (Good risk) had median OS of 3.1, 8.8, and 16.5 months respectively, p< 0.0001. The corresponding median OS for the validation series (n = 44) were 3.3, 8.1, and 13.3 months, p = 0.023. Platinum – based regimens were associated with OS benefit compared to other combination regimens and to single agents, such benefit was retained when this factor was included in multivariate analysis (HR: 3.1, 95% CI: 1.82- 4.98, p< 0.0001). In addition, freedom of progression at 6 months from initiation of second- line therapy correlated with improved survival compared to progression within 6 months; median OS 13.9 and 6.6 months respectively, p< 0.0001. Conclusions: We proposed and validated a prognostic model for patients with metastatic UCC who are eligible for second-line therapy. The proposed model may prove helpful for risk-stratification. Furthermore, our data suggest that testing second- line platinum-based regimens in randomized trials is warranted.
Laser versus electrical en bloc resection of bladder tumors: Results of a European multicenter study (EBRUC).
Authors: Kramer Mario W. , Martov Alexey , Baykov Nikolay , Klein Jan , Rassweiler Jens J. , Lusuardi Lukas , Janetschek Guenter , Hurle Rodolfo , Wolters Mathias , Abbas Mahmoud , Leitenberger Armin , Riedl Markus , Nagele Udo , Merseburger Axel S. , Kuczyk Markus A. , Babjuk Marek , Herrmann Thomas R. W. 
Published: February 2017

310 Background: The quality of transurethral resection of bladder tumors strongly determines patient’s tumor after-care and prognosis. En bloc resection of bladder tumors (ERBT) might improve staging quality, perioperative morbidity and influence tumor recurrence. This is the first European multi-center study which was initiated by ESUT and was conducted to evaluate the safety, efficacy and recurrence rates of electrical vs. laser ERBT. Methods: Transurethral ERBT was performed on 221 prospectively collected patients in six academic centers with either monopolar/bipolar current or holmium/thulium laser energy. Staging quality measured by detrusor muscle involvement, various perioperative/surgical parameters and 12 months follow-up data were analyzed. Results: 156 and 65 patients were treated with electrical and laser ERBT, respectively. Median tumor size was 2.1 cm with biggest up to 5 cm. Detrusor muscle was available in 97.3%. A switch to conventional TURBT was significantly more frequent in the electrical ERBT group (26.3% vs. 1.5%, p<0.001). Median operation duration (25 min), postoperative irrigation (1 day) and catheterization time (2 days) as well as hospitalization (3 days) were similar in both groups. Overall complication rate was low (Clavien ≥3, n=6 (2.7%)). Hemoglobin was significantly more decreased after electrical ERBT (p=0.0013), however overall hemoglobin loss was not clinically relevant (0.38 g/dl). 148 patients with first diagnosis of urothelium carcinoma of the bladder were followed for 12 months of which 33 (22.3%) recurred. 63.6% of recurrences occurred out of the ERBT resection field. No difference was noticed between both ERBT groups. Conclusions: ERBT is safe and reliable regardless of the energy source used and offers high quality resections of tumors >1 cm. Recurrence rates did not differ within both groups although the majority of recurrences were noticed out of the ERBT resection field. Laser device might be an alternative for the treatment of patients with higher risk of postoperative bleeding due to its efficient hemostatic effect.
Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.
Authors: Choudhury Noura , Campanile Alexa , Wade James Lloyd , Antic Tatjana , Stadler Walter Michael , Nakamura Yusuke , O'Donnell Peter H. 
Published: February 2017

312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
Expression of PDL1 (B7-H1) before and after neoadjuvant chemotherapy (NAC) in urothelial carcinoma.
Authors: Alva Ajjai Shivaram , McDaniel Andrew , Zhan Tianyu , Xiao Hong , Chinnaiyan Arul M. , Lee Cheryl T. , Mehra Rohit 
Published: February 2017

313 Background: Expression of the co-stimulatory ligand PDL1 (B7-H1) of the PD-PDL immune checkpoint on tumor cells enables evasion of anti-tumor immunity. The PD-PDL checkpoint is a therapeutic target in UC. We sought to characterize the impact of cytotoxic NAC on PDL1 expression before and after NAC to inform optimal sequencing/combination strategies of immune/cytotoxic therapies. Methods: Immunohistochemical (IHC) staining for PDL1 was performed using a murine anti-B7-H1 monoclonal antibody (clone 5H1) on a tissue microarray with matched pre-NAC T1/T2 transurethral resection (TURBT) samples (T0=2; Tx=1; T1=1; T2=23, T3=11; T4=2) and post-NAC cystectomy samples (pT0N0=15, TisN0=1, T1N0=3, T2N0=6, T3N0=9, T3Nx=1, T4Nx=1, T2N1=1, T3N2, T4N2=1, T3N3=1) from 40 patients (pts) treated from 1999-2011 at the University of Michigan. NAC was cisplatin-based in 13 pts and carboplatin-based in 26 pts. IHC was scored as the product of tumor cell staining intensity (0-3) and percentage of cells positive (0-100). Correlations of T stage at TURBT with the score were analyzed with unpaired t-test and Wilcoxon test. ANOVA analysis and paired t-tests were done to correlate pStage with the score. Results: PDL1 expression was significantly higher in post-NAC cystectomy specimens (mean IHC product score= 217.5) compared to the matched pre-NAC TUR specimens (mean IHC product score= 176.6, p value=0.0196 by Student's paired T test). Among the 21 non-pT0 pts with data at both time-points, PDL1 expression increased after NAC in 16 pts. The % of PDL1 positive cells in the residual tissue increased in 15 pts. The PDL1 expression product score in pre-NAC or post-NAC tissue did not correlate with clinical or pathologic stage, or with recurrence-free or overall survival. Conclusions: PDL1 expression in locally advanced UC in pts receiving NAC did not correlate with clinical outcomes in our small cohort. However, the expression of PDL1 in post-NAC tissue was elevated compared to pre-NAC. The increased PDL1 expression following NAC informs rational combinations and sequencing of cytotoxic chemotherapy with anti-PD1/PDL1 immunotherapies in UC particularly in adjuvant therapy for residual disease after neoadjuvant therapy.
Correlation of the clinical frailty scale with long-term survival after radical cystectomy.
Authors: Kramer Mario W. , Hennig Martin JP , von Klot Christoph A. J. , Wegener Gerd , Heinisch Annika , Peters Inga , Herrmann Thomas R. W. , Kuczyk Markus A. , Tezval Hossein , Merseburger Axel S. 
Published: February 2017

314 Background: Demographic changes account for an increasingly large proportion of elderly patients with urothelial carcinoma of the bladder. It remains under debate to which extent a patient might benefit from major surgery such as the radical cystectomy. Current tools for preoperative assessment of biological age might be of limited significance. The frailty concept, which refers to a biological syndrome of decreased reserve to stressors and resistance to stressors, has gained recent recognition for measuring patient’s physiological reserve and has been linked to adverse outcomes after surgery. Methods: Clinical, surgical and pathological data of patients undergoing radical cystectomy and lymph node dissection at Hannover Medical School with a minimum age of 60 years were retrospectively collected from 2000 to 2010. Frailty was assessed using the clinical frailty scale by Rockwood et al. derived from the Canadian Study of Health and Aging (CSHA). The relationship between frailty and various risk assessment tools such as the ASA-score, Charlson Comorbidity Index (CCI) and Karnofsky score (KS) in regard of long-term follow-up data was analyzed. Results: Our cohort included 255 patients (male 197, female 58). Mean age was 70 years (SD ±6.14). Patients were categorized into “not frail” (n=53, 21%), “vulnerable and mildly frail” (n=156, 61%), and “moderately/severely frail” (n=46, 18%). Higher CSHA was associated with increased CCI and higher rate of perioperative complications (each p<0.001). 179 (70%) patients had died during follow-up (mean follow-up, 61 months). Median survival differed significantly between groups (68 vs. 29 vs. 12 months, p<0.0001). In univariate analyses ASA, CCI, KI, and CSHA correlated with long-term survival (each p<0.001). In multivariate analysis only CSHA remained predictor of survival besides age, lymph node involvement, resection margins, and T-stage. Conclusions: The clinical frailty scale is an easy to use tool. It correlates with survival and perioperative complications after radical cystectomy. This study warrants further assessment of the frailty concept; however, it still has to be determined whether the clinical frailty scale is superior to other frailty assessment schemes.
Patient-derived xenograft platform to guide precision medicine in bladder cancer.
Authors: Pan Chong-Xian , Zhang Hongyong , Lin Tzu-yin , Tepper Clifford , Keck James , Ghosh Paramita , Airhart Susan D. , Bult Carol J. , Gandara David R. , Evans Christopher P. , Liu Edison T. , deVere White Ralph 
Published: February 2017

315 Background: The prognosis for bladder cancer has not changed in 30 years. No targeted agents have been approved even though reproducible genetic abnormalities have been identified. The goal of this project was to develop and characterize a patient-derived xenograft (PDX) platform to determine the efficacy of molecularly guided targeted and chemotherapy therapy, drug re-purpose, study resistance mechanisms, and design novel therapy to overcome resistance. Methods: PDXs were developed from direct implantation of uncultured patient bladder cancer specimens into immunodeficient NSG mice. Deep sequencing in combination with computational biology was performed to characterize PDXs and identify druggable genetic aberrations that guided efficacy screening and mechanistic studies. Results: Nineteen PDXs have been established with annotated clinical information. PDXs retained morphology and 92-97% genetic aberrations of parental patient cancers. Deep sequencing revealed multiple druggable genetic aberrations, including the fibroblast growth factor receptor 3 (FGFR3) and other tyrosine kinase receptor pathways. Compared to the progression-free survival (PFS) of 9.5 days in the control arm, matched therapy with an FGFR3 inhibitor BGJ398 prolonged PFS to 18.5 days (p=2.61 X 10-6) in PDXs overexpressing FGFR3. Serial biopsies during treatment revealed reactivation of the downstream pathways coincided with development of resistance while targeting these downstream effectors reversed resistance (12 vs. 22 days, p=0.001). Efficacy studies also revealed that PDXs had differential response to chemotherapeutic drugs that could potentially guide selection of chemotherapeutic drugs for first- and second-line therapies. To determine the clinical applicability of non-myoinvasive bladder cancer, we further developed an orthotopic PDX model that mimiced disease progression to invasive and metastatic bladder cancer. Conclusions: The PDX platform allows screening for multiple targeted therapy, chemotherapy or combinations simultaneously for the most efficacious drugs or combination, and serial biopsies during treatment to study drug resistance, a task not possibly replicable at the clinical setting.
Quality of life in long-term survivors of muscle-invasive bladder cancer.
Authors: Mak Kimberley S. , Smith Angela , Eidelman Alec , Clayman Rebecca Helen , Cheng Jed-Sian , Matthews Jonathan , Niemierko Andrzej , Nielsen Matthew Edward , Feldman Adam S. , Lee Richard J. , Zietman Anthony L. , Shipley William U. , Chen Ronald C. , Milowsky Matthew I. , Efstathiou Jason Alexander 
Published: February 2017

319 Background: Health-related quality of life (QOL) is not well-studied in survivors of muscle-invasive bladder cancer (MIBC). This cross-sectional multi-institutional study compared long-term QOL in MIBC patients treated with bladder-sparing trimodality therapy (TMT) vs. radical cystectomy (RC). Methods: Patients with non-metastatic cT2-T4 MIBC, diagnosed in 1990-2011 and disease-free for ≥2 years were identified. A questionnaire using validated general and disease-specific QOL instruments was administered (score ranges: 0-100). Results: Of 226 eligible patients, 173 returned the questionnaire for a response rate of 77%. Sixty-four received TMT and 109 RC (89 with ileal conduit and 18 with neobladder diversions). The median time from diagnosis to questionnaire was 9 vs. 6 years, respectively (p=0.009). Comparing TMT to RC, there was no significant difference in age at diagnosis or questionnaire, gender, smoking, clinical stage or comorbidities. On univariable analysis (UVA), patients who received TMT had significantly better general QOL than patients who received RC by 4.8 points on the EQ-5D 3L and 7.4 points on the EORTC QLQ-C30 (Table). On multivariable analysis (MVA), adjusting for age, time from diagnosis, year of treatment, gender and comorbidities, patients who received TMT had significantly better general QOL by an average 6-7 points. On MVA, TMT was associated with significantly better bowel function by an average 4.5 points on the EPIC bowel function subscale, but with no difference in bowel bother. Urinary QOL was equivalent between groups, as measured by the EORTC QLQ-BLM30. Conclusions: While both TMT and RC provide good long-term outcomes, TMT appears to be associated with higher general QOL and bowel function compared to RC. [Table: see text]