bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality-of-life (QoL) in RANGE: A phase 3 study of ramucirumab (RAM) plus docetaxel (DOC) versus placebo (P) plus DOC in platinum-refractory locally advanced or metastatic urothelial carcinoma (UC).
Authors: Necchi Andrea , Nishiyama Hiroyuki , Matsubara Nobuaki , Lee Jae-Lyun , Petrylak Daniel Peter , De Wit Ronald , Drakaki Alexandra , Liepa Astra M. , Zimmermann Annamaria , Bell-McGuinn Katherine M. , Powles Thomas 
Published: February 2018

419 Background: RAM + DOC in RANGE (NCT02426125) improved progression free survival (hazard ratio [HR] = 0.757) with a higher objective response rate (24.5% vs 14%) and an acceptable safety profile (Petrylak, et al Lancet 2017). QoL was a secondary objective. Methods: Patients (pts) whose UC progressed following platinum-based therapy were randomized to receive RAM (10 mg/kg) + DOC (75 mg/m2) or P + DOC on Day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity with a maximum of 10 cycles for DOC. Pts completed the EORTC QLQ-C30 (v3) prior to each cycle & at the 30-day follow up visit. QoL scales were analyzed for: 1) rates of improved/stable scores (compared with Fisher’s exact test) & 2) time to sustained deterioration (TtD), defined as randomization to first worsening with no subsequent non-worsened assessment (compared with unstratified log-rank test). A ≥10 point change (on 100-point scale) was deemed clinically meaningful. Results: 530 pts were randomized. 254/263 (97%) RAM-DOC & 260/267 (97%) P-DOC pts provided baseline (BL) QoL data & ≥85% for post-BL, on-therapy assessments. Median number of cycles was 4 for RAM-DOC & 3 for P-DOC. Mean BL scores were similar between arms & indicated greatest impairment for global QoL, fatigue, pain, & insomnia. For all scales, rates of improved/stable scores were not different, except for pain at Cycles 4 & 7 where rates were higher for RAM-DOC (p < 0.05). Relative to other QoL scales, pain generally had highest rates of improved scores in both arms (14-25% for RAM-DOC & 8-24% for P-DOC for Cycles 1-4). In a post hoc analysis, Cycles 1-4 rates of improved pain scores were 31-32% for RAM-DOC & 14-26% for P-DOC in tumor responders, but 17-29% for RAM-DOC & 16-28% for P-DOC in pts with stable disease. For TtD, 14/15 QoL scales had HRs < 1, indicating similar or numerically longer TtD in QoL for RAM-DOC (HRs 0.67- 1.06; all 95% confidence intervals included 1). Conclusions: The addition of RAM to DOC for platinum-refractory UC pts did not adversely impact QoL relative to P-DOC. Trends in improved TtD and improved rates of pain associated with tumor response favored RAM-DOC. Clinical trial information: NCT02426125.
German health service research group IQUO present daily routine results of adjuvant instillation therapy for the intermediate risk group NMIBC in out patient office management.
Authors: Luedecke Gerson , Geiges Goetz , Lange Monica , Schulze Matthias ,   Interessenverband zur Qualitätssicherung der Arbeit niedergelassener Urologie-Onkologen in Deutschland e.V. (IQUO)
Published: February 2018

423 Background: The international guidelines for bladder cancer define adjuvant chemo-instillation therapy in intermediate risk NMIBC as standard of care. The health service research foundation IQUO has prospectively checked how strictly German urologists identify and follow the guidelines for intermediate risk BC with adjuvant Mitomycin C indication in daily routine. Methods: Via the Internet based data collection platform of the IQUO uro-oncology specialized office based urologists collected from 2012 to 2015 prospectively adjuvant NMIBC patients treated with Mitomycin C 20mg/20ml in a cohort analysis. Results: 854 patients were included in this study (19% female, 81% male). Median age 73 years, range (30-93). Recurrence risk was classified in 18.7% high-, 33.6% intermediate-, 37.2% low- and 10.5% minimal risk. Progression risk was classified in 3.4% high-, 16.7% intermediate-, 53.3% low- and 26.6% minimal risk. Early instillation was performed in 54% of the patients. The starting point of adjuvant instillation varied form day 1 after TUR to longer than 21 days. The induction phase varied from 4 weeks in minimum (12.9%) to 6 weeks (31.1%), 8 weeks (34%), 12 weeks (4.9%) and 17.1% individually. The maintenance was given in 68.9% of the patients varying from 3 month up to 3 years. Differences in treatment between the genders were not observed. The analysis of accordance to the guidelines in respect to adjuvant instillation in intermediate risk NMIBC showed a 70.7% accordance, an over treatment of 10.5%, and an under treatment of 18.7%. Conclusions: We have found a tremendous heterogeneity in the practiced adjuvant Chemo-Instillation therapy in NMIBC patients. This included early instillation post-operatively, adjuvant onset time point and duration of induction therapy and maintenance. The consequence of this health service research results is that standardization and education is one of our main duties for the near future to ensure consequent, complete and correct adjuvant treatment in intermediate NMIBC patients to ensure effectiveness.
Preoperative chronic kidney disease to predict oncological outcomes after radical cystectomy in patients with muscle-invasive bladder cancer.
Authors: Hatakeyama Shingo , Hamano Itsuto , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Kawaguchi Toshiaki , Ohyama Chikara 
Published: February 2018

427 Background: Chronic kidney disease (CKD) is common in elderly patients with bladder cancer. In addition, increasing evidence has suggested that preoperative renal insufficiency indicates poor prognosis in bladder cancer. We aimed to evaluate the impact of CKD on oncologic outcomes in muscle-invasive bladder cancer patients who underwent radical cystectomy. Methods: A total of 581 patients who underwent radical cystectomy at four medical centers between January 1995 and February 2017 were examined retrospectively. We investigated oncologic outcomes, including progression-free, cancer-specific, and overall survival (PFS, CSS, and OS, respectively) stratified by preoperative CKD status (CKD vs. non-CKD). We performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) to evaluate the impact of preoperative CKD on prognosis and developed the prognostic factor-based risk stratification nomogram. Results: Of the 581 patients, 215 (37%) were diagnosed with CKD before radical cystectomy. Before the background adjustment, PFS, CSS, and OS after radical cystectomy were significantly lower in the CKD group compared to the non-CKD group. Background-adjusted IPTW analysis showed that preoperative CKD was significantly associated with poor PFS, CSS, and OS after radical cystectomy. The nomogram for predicting 5-year PFS and OS probability showed significant correlation with actual PFS and OS ( c-index = 0.73 and 0.77, respectively). Conclusions: Muscle-invasive bladder cancer patients with preoperative CKD had a significantly lower survival probability than those without CKD.
Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study.
Authors: Petrylak Daniel Peter , Smith David C. , Flaig Thomas W. , Zhang Jingsong , Sridhar Srikala S. , Ruether Joseph D. , Plimack Elizabeth R. , Merchan Jaime R. , Quinn David I. , Kilari Deepak , Srinivas Sandy , Baranda Joaquina Celebre , Lang Joshua Michael , Milowsky Matthew I. , Galsky Matt D. , Spira Alexander I. , Gartner Elaina M. , Wu Chunzhang , Melhem-Bertrandt Amal , Rosenberg Jonathan E. 
Published: February 2018

431 Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was < 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999.
T-cell receptor sequencing of bladder tumor infiltrating lymphocytes to reveal a clonal immune response.
Authors: Sankin Alexander , Chand Damini , Schoenberg Mark P. , Zang Xingxing 
Published: February 2018

437 Background: High T cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer (Funt et al ASCO 2016). We hypothesized that T cell repertoire is more clonal in tumors than in benign inflammation. Methods: After obtaining IRB approval, we prospectively identified 12 patients with bladder lesions at Montefiore Medical Center/Albert Einstein College of Medicine undergoing transurethral resection of bladder tumor (TURBT). Specimens collected at the time of TURBT were stored at -80C. After DNA extraction, high throughput sequencing of the CDR3 region of the TCR beta chain using the ImmunoSEQ assay (Adaptive Biotechnologies) was performed. Various parameters such as T infiltrating lymphocyte (TIL) percentage, total productive rearrangements, unique productive rearrangements, and maximum frequency of TCR clone were assessed. Results: 9/12 specimens were malignant (UC+) and 3/12 specimens were benign (UC-). There was an even distribution of specimens across all pathologic stages: 3/12 were T0, 3/12 were Ta, 3/12 were T1, and 3/12 were T2 or greater. The median number of T cells sequenced in UC+ and UC- specimens was 5,569 and 25,872 respectively. The median number of unique TCR rearrangements sequenced in UC+ and UC- specimens was 3,069 and 9,680, respectively. The median TIL percentage in UC+ and UC- specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as indicated by maximum productive frequency of up to 17% as opposed to a maximum productive frequency of 2% in UC- specimens. Conclusions: Primary urothelial tumors contain clonally expanded T cell populations that are not present in benign urothelium. Our data supports the hypothesis that bladder tumors induce a clonal T cell host response against tumor derived antigens. In contrast, benign inflammatory response does not appear to demonstrate any T cell clonal dominance. Future studies to identify tumor specific antigens that contribute to clonal expansion and predict therapeutic efficacy of immunotherapy will be of clinical significance.
Efficacy and tolerability of Paclitaxel-Gemcitabine therapy for urothelial carcinoma in patients who have received prior platinum-based chemotherapy.
Authors: Tomisaki Ikko , Minato Akinori , Fujimoto Naohiro 
Published: February 2018

443 Background: Although platinum-based chemotherapy is the standard regimen as first line chemotherapy for urothelial carcinoma, the optimal second line regimen has not been yet established. The objective of this study was to evaluate the efficacy and safety of combination chemotherapy with paclitaxel (PTX) and gemcitabine (GEM) (PG therapy) for patients who have received prior platinum-based chemotherapy. Methods: We reviewed consecutive patients with locally advanced or metastatic urothelial carcinoma who received PG therapy after platinum-based chemotherapy. Doses and schedule of PG therapy were as follows; PTX, 200mg/m2on day 1, GEM, 1000/m2 on days 1, 8, 15, repeated every 21 days. Imaging studies to assess the efficacy was repeated every 2 cycles of the therapy. Results: We identified 52 eligible patients. Of 52 patients, complete response (CR), partial response (PR), stable disease and progressive disease were observed in 2 (3.8%), 14 (26.9%), 18 (34.6%) and 18 (34.6%), respectively. With the median follow-up period of 9.8(IQR 5.5-16.3) months, the median progression free survival (PFS) after PG therapy was 4.7 months [95% confidence interval (CI), 3.6-5.8] and median overall survival (OS) after PG therapy was 11.6 months (95%CI:8.6-15.3). The sensitivity to PG therapy differed in disease sites, the response rate (CR+PR) of primary site, metastases in lymph nodes, lung, bone and liver was 8.3%, 48.7%, 29.4%, 0% and 33.3%, respectively. The response (CR or PR) to PG therapy [Hazard ratio (HR);0.42, 95% CI 0.18-0.95, p=0.04] and primary site (upper urinary tract) (HR;2.24, 95% CI 1.09-4.62, p=0.03) were associated with longer and shorter PFS, respectively. The response to PG therapy was also identified as a significant independent predictive factor for longer OS (HR;0.31, 95% CI 0.12-0.77, p=0.01). Myelosuppression was the most common adverse event. Only one patient discontinued the treatment due to an adverse event and there were no therapy-related deaths. Conclusions: PG therapy was safe and effective as second line regimen after platinum-based chemotherapy for urothelial carcinoma, especially in primary, lymph node and lung lesions.
Preliminary results from patients with urothelial carcinoma (UC) in a phase 1A/1B study of bgb-A317, an anti-PD-1 monoclonal antibody.
Authors: Sandhu Shahneen Kaur , Hill Andrew Graham , Gan Hui Kong , Friedlander Michael , Voskoboynik Mark , Barlow Paula , Townsend Amanda Rose , Song James , Zhang Yun , Shen Zhirong , Qi Qinzhou , Desai Jayesh 
Published: February 2018

445 Background: Monoclonal antibodies (mAb) against programmed cell death-1 (PD-1) have demonstrated antitumor activity across multiple malignancies. BGB-A317 is a humanized IgG4 mAb with high affinity and binding specificity for PD-1. Previous reports from an ongoing Phase 1A/1B study (NCT02407990) in patients with advanced solid tumors suggested that BGB-A317 was generally well tolerated and had antitumor activity in multiple tumor types. Here, we present the preliminary results from a subset of patients with UC enrolled in this study. Methods: Patients with UC received intravenous BGB-A317 at doses of 2, 5, 10 mg/kg Q2W or Q3W and 200 mg Q3W. Tumor cell (TC) and immune cell (IC) PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Safety and tolerability was assessed by monitoring adverse events (AEs) and antitumor effects were assessed by RECIST v1.1 criteria. Results: As of 8 June 2017, 15 patients with UC (median age, 72 yr [range: 39–79]) received BGB-A317 during phases 1A (n = 8) and 1B (n = 7). All patients were Caucasian and 13 patients were male; the median number of prior systemic anticancer therapies was 1 (range: 0–4). Median duration of treatment was 115 d (range: 27–476); 6 patients remain on treatment. The most common treatment-related AEs (TRAEs) were fatigue (n = 5) and rash (n = 3); grade ≥3 TRAEs included fatigue (n = 1), and hyperglycemia and type 1 diabetes mellitus (T1DM; n = 1). Serious TRAEs occurred in 2 patients (infusion-related reaction [n = 1]; hyperglycemia and T1DM [n = 1]). All patients were evaluable for response assessment. Confirmed complete and partial responses occurred in 1 and 3 patients, respectively, for a response rate of 27%; the disease control rate (CR+PR+SD) was 53%. Nine samples were available for PD-L1 evaluation. Responses were observed in 3 of 6 patients with PD-L1+ tumors (defined as ≥25% TC or IC expressing PD-L1 by IHC) while 1 in 3 patients with PD-L1– tumors responded. Conclusions: BGB-A317 was generally well tolerated in patients with UC and objective responses were observed in both PD-L1+ and PD-L1– diseases. BGB-A317 is currently being investigated in China as monotherapy for patients with PD-L1+ UC (CTR20170071). Clinical trial information: NCT02407990.
Identifying high surgical risk in muscle-invasive bladder cancer (MIBC) patients undergoing radical cystectomy (RC).
Authors: Marqueen Kathryn E. , Waingankar Nikhil , Sfakianos John , Mehrazin Reza , Niglio Scot Anthony , Audenet François , Jia Rachel , Mazumdar Madhu , Ferket Bart , Galsky Matt D. 
Published: February 2018

460 Background: Although RC is the standard treatment for MIBC, it is associated with non-negligible morbidity and mortality. Given the advanced age and prevalence of comorbidities in MIBC patients, many are suboptimal RC candidates. We sought to develop a prediction rule for determining high surgical risk using routinely available pre-surgical variables. Methods: We identified N=8,634 patients with MIBC (cT2-T4aN0M0) who underwent RC, without perioperative chemotherapy, within the National Cancer Database (2003-2012). Using multi-state modeling, we calculated time spent in 3 health states: hospitalized, discharged and death over 90 days post-RC. Predictors were selected in a stepwise manner. Cross validation was performed leaving one of 6 geographic regions out to assess model performance. Time spent in each state was weighted by utility (0=death, 1=full health) to determine 90d quality-adjusted survival (QAS) as a composite of morbidity and mortality. Results: Median age: 69y (IQR 62-78), mean length of stay: 10±12d, and 90d mortality: 654/8,634 (7.6%). Increasing age, cT stage, Charlson comorbidity index (CCI) and lower hospital RC volume were associated with greater 90d mortality (Table). C-statistics of 0.57-0.73 and calibration slopes of 0.54-1.37 (1=perfect) were sufficient across the regions. Our model predicted 25% of patients had a 90d mortality >10%; observed 90d mortality in this group was 14.0% (95% CI 12.5-15.5). Mean QAS was 63d (range 43-68). Conclusions: We developed a multi-state model to identify high post-RC risk that may ultimately help to identify patients for ‘prehabilitation’ strategies and/or inform standard definitions of ‘cystectomy ineligibility’ for clinical trials. [Table: see text]
Combination therapy of low-dose gemcitabine and paclitaxel in every 4 weeks for patients with platinum-resistant urothelial cancer whose performance status is 2 or 3.
Authors: Matsuo Tomohiro , Miyata Yasuyoshi , Sagara Yuji , Ohba Kojiro , Sakai Hideki 
Published: February 2018

462 Background: Platinum-based regimens are standard therapy for advanced urothelial cancer (UC). However, second-line chemotherapy is still not established. Therefore, best supportive care is often selected in patients with poor performance status (PS). In our hospital, combination therapy of low-dose gemcitabine and paclitaxel every 4 weeks is administered as second-line therapy for platinum-resistant patients with PS 2 or 3. We investigated the quality of life (QoL) and safety of our regimen in these patients. Methods: Forty-two advanced UC patients were treated with gemcitabine (700 mg/m2 on day 1) and paclitaxel (70 mg/m2 on day 1) every 4 weeks (experimental group). The QoL was evaluated using the short-form survey (SF)-36, and the data were collected on the day before the first cycle was started and 8 weeks after starting the therapy. In addition, survival analysis was performed between these patients and 30 patients who received no second-line therapy (control group). Results: In experimental group, one patient showed grade 3 anemia after the treatment. However, this patient also had severe hematuria before staring of the therapy. No patient had severe adverse events (grade 3 and higher) because of this therapy. The QoL score decreased after the therapy; however, the difference was not significant. With regard to efficacy, partial response was found in two patients, and the mean/SD survival period of the experimental group was 9.2/7.2 months. This period was significantly (P < 0.01) longer than that in the control group (5.8/2.4 months). In addition, 13 (31.0%) and 6 patients (14.3%) survived over 12 and 18 months, respectively. Conclusions: Combined therapy of low-dose gemcitabine and paclitaxel every 4 weeks was well tolerated, and the patient’s QoL was maintained after treatment. Some patients showed relatively long survival periods. We suggest that this treatment regimen is worthy of consideration as second-line therapy for patients with advanced UC with PS 2 or 3.
Evaluation of a 29 gene classifier for basal/non basal prediction in muscle-invasive bladder cancer FFPE samples.
Authors: Allory Yves , Sirab Nanor , Drubay Damien , Gentien David , De ReyniÃ¨s AurÃ©lien , Albaud Benoit , Kamoun Aurélie , Soyeux Pascale , Maille Pascale , Lebret Thierry , Benhamou Simone , Paoletti Xavier , Radvanyi Francois 
Published: February 2018

467 Background: Recent and independent muscle-invasive bladder cancer (MIBC) molecular classifications identified the basal / squamous-like (BASQ) tumours as an intrinsic and robust subtype, with a poor outcome and possible chemosensitivity to cisplatin based regimen, making mandatory the development of a diagnostic tool for their identification in routine samples. Our study aimed to evaluate the diagnostic accuracy of a Nanostring classifier for tumor subtype prediction on FPPE specimens. Methods: Two series of MIBC were used (CIT n = 51 & Stransky n = 22) for which BASQ tumours were identified previously using Affymetrix transcriptome data obtained from frozen samples (Rebouissou, Science Trans Med 2014). 29 genes were selected to predict the basal subtype, RNA expression of matched frozen and FFPE samples was studied using Nanostring technology. To define the classifiers for Affymetrix, frozen and FFPE Nanostring expression matrix on CIT samples the centroid of each cluster was calculated using the expression of 29 genes. Internal validation used leave-one-out cross-validation to train and test the prediction accuracy of the new classifier. For external validation, the CIT samples were used as training set and the Stransky samples as validation set. Predictive accuracy expressed as percentage of correctly classified samples is provided. Results: Correlations between Affymetrix, frozen and FFPE Nanostring data set were checked for gene expression and samples. Using CIT samples as train and test set, the predictive accuracy for BASQ tumour identification was for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers, 90.20% [78.59%; 96.74%], 88.24% [76.13%; 95.56%] and 92.16% [81.12%; 97.82%], respectively. Using training on CIT samples and test on Stransky samples, this predictive accuracy was 90.91% [70.84%; 98.88%] both for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers. Conclusions: The 29 gene expression Nanostring codeset was able to identify reliably basal / squamous like tumours on FFPE samples from MIBC in comparison with the gold standard approach based on transcriptomic profile, appearing as a promising diagnostic tool.