bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC).
Authors: Birtle Alison Jane , Chester John David , Jones Robert Jones , Johnson Mark , Hill Michaela , Bryan Richard T , Catto James , Donovan Jenny , French Ann , Harris Chris , Keeley Francis , Kockelbergh Roger , Powles Thomas , Todd Rachel , Tregellas Lucy , Wilson Caroline , Winterbottom Andrew , Lewis Rebecca , Hall Emma ,   On Behalf of the POUT Investigators
Published: February 2018

407 Background: The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC. Methods: Pts (max n = 345) ≤90 days post NU were randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p < 0.001) early stopping rules for efficacy & inefficacy. Secondary endpoints included metastasis-free survival (PFS), overall survival (OS), toxicity & quality of life. Results: Between May 2012 & Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 05/09/2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Pts had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0;. Grade ≥3 toxicities were reported in 60% chemotherapy pts & 24% surveillance pts. 47/123 (surveillance) & 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favour of chemotherapy (log-rank p = 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). PFS favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003). Conclusions: Adjuvant chemotherapy improved PFS in UTUC. POUT is the largest randomised trial in this pt population; the trial was terminated early because of efficacy favouring the chemotherapy arm. Whilst follow up for OS continues, this should be considered a new standard of care in these patients. Clinical trial information: ISRCTN98387754.
Selective bladder preservation with twice-daily radiation plus 5-flourouracil/cisplatin (FCT) or daily radiation plus gemcitabine (GD) for patients with muscle invasive bladder cancer: Primary results of NRG/RTOG 0712—A randomized phase 2 multicenter trial.
Authors: Coen John J , Zhang Peixin , Saylor Philip James , Lee Cheryl T. , Wu Chin-Lee , Parker William , Lautenschlaeger Tim , Zietman Anthony L. , Efstathiou Jason A. , Jani Ashesh B. , Kucuk Omer , Souhami Luis , Rodgers Joseph P , Sandler Howard M. , Shipley William U. 
Published: February 2018

408 Background: To assess GD or FCT as the chemoradiation (CRT) component of a bladder sparing regimen. Methods: Patients with T2-4a bladder cancer were randomized. Patients had a maximal transurethral resection and induction CRT to 40 Gy followed by cystoscopic assessment. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others were offered cystectomy and no further CRT. Adjuvant gemcitabine/cisplatin chemotherapy was subsequently administered. The primary endpoint was the rate of distant metastasis at 3 years (DM3). Toxicity and other efficacy related endpoints including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3) were also assessed. Using the Clopper-Pearson method, the study required 32 patients per arm, with a benchmark DM3 of 25% and a 1-sided significance level of 0.1. If both arms meet this benchmark, toxicity will be used to select a regimen for future study. This study was not designed to compare arms. Results: From 12/2008 to 4/2014, 70 patients were enrolled; 66 were eligible for analysis (33 per arm). Median follow-up was 4.3 years. DM3 was 22% and 16% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. CR rates were 88% and 78%, respectively. Of 33 patients in the FCT group, 32 (97%) completed induction, 27 (93%) completed induction and consolidation, and 18 (55%) completed the entire protocol. Of 33 patients in the GD group, these figures were 31 (94%), 23 (92%), and 16 (49%), respectively. Of 33 patients in the FCT group, 21 (64%) had grade 3-4 toxicity during protocol treatment with 18 (55%), 2 (6%) and 2 (6%) experiencing hematologic, GI and GU toxicity, respectively. For 33 patients in the GD group, these figures were 18 (55%) overall and 14 (43%), 3 (9%) and 2 (6%), respectively. Conclusions: Both regimens are promising, given DM3 rates < 25%. As there was less toxicity in the GD arm, it would be reasonable to consider a gemcitabine based option as well as a cisplatin based regimen for future trials. Daily radiation may be as effective as twice-daily radiation, which may broaden appeal. Clinical trial information: NCT00777491.
New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab.
Authors: Pond Gregory Russell , Niegisch Guenter , Rosenberg Jonathan E. , Dreicer Robert , Powles Thomas , Necchi Andrea , Wei Xiao X. , Grivas Petros , Balar Arjun Vasant , Galsky Matt D. , Srinivas Sandy , Choueiri Toni K. , Bellmunt Joaquim , Bajorin Dean F. , Sonpavde Guru 
Published: February 2018

413 Background: Prognostic factors for overall survival (OS) have been identified in pts receiving post-platinum chemotherapy for advanced UC, but it is unknown whether these factors and/or others optimally predict OS for pts treated with PD1/PD-L1 inhibitor therapy. Methods: Pt level data from two UC salvage trials evaluating atezolizumab were used: IMvigor210 (n = 310) for training and PCD4989g (n = 95) for validation. Univariable and multivariable Cox regression analyses were performed to evaluate the association of the prognostic factors recognized in the chemotherapy setting (ECOG performance status [ECOG-PS], liver metastasis (LM), anemia, treatment-free interval, albumin), neutrophil-lymphocyte ratio (NLR), eosinophil count, platelet count (PLT), site of primary/metastases, stage at diagnosis, smoking, LDH, prior therapies and immune cell PD-L1 status by IHC with OS. Clinical factors were dichotomous and lab values normalized by logarithmic transformation as needed. Stepwise selection was employed to propose an optimal model using the training dataset; pts were then categorized by number of risk factors. Concordance, discrimination (c-statistic) and calibration were assessed in the validation dataset using bootstrap analyses. Results: The factors included in the optimal prognostic model for OS were: ECOG-PS 1 vs. 0 (HR 1.64 [95% CI: 1.20, 2.24], p = 0.002), LM (1.45 [1.08, 1.94], p = 0.014), PLT (1.73 [1.14, 2.61], p = 0.010), NLR (1.84 [1.45, 2.34], p < 0.001), LDH (1.54 [1.19, 1.99], p = < 0.001) and anemia (HR = 1.60 [1.17, 2.21] p = 0.004). The c-statistic was 0.690 (95% CI = 0.649-0.715) and 0.759 (0.694-0.795) in the training and validation datasets, respectively. 1-year OS of pts in the training and the validation cohorts were similar. PD-L1 score was statistically significant when adjusted for the optimal model, but did not improve clinical interpretability (c-statistic = 0.698). Conclusions: A new validated 6-factor prognostic model for OS including ECOG-PS, LM, PLT, NLR, LDH and anemia is proposed in the setting of post-platinum atezolizumab for advanced UC. Applicability of the model to other PD1/PD-L1 inhibitors and PD-L1 IHC assays warrant investigation.
A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: A Japanese retrospective multi-institutional study.
Authors: Inoue Takamitsu , Miyazaki Jun , Ichioka Daishi , Narita Shintaro , Kageyama Susumu , Sugimoto Mikio , Mitsuzuka Koji , Kinoshita Hidefumi , Kikuchi Eiji , Matsui Yoshiyuki , Fujie Keiko , Habuchi Tomonori , Nishiyama Hiroyuki 
Published: February 2018

420 Background: To compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma. Methods: We retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR≥60 mL/min/1.73 m2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR≥60 mL/min/1.73 m2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 45, 18.4%); and a solitary-functioning kidney with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 80, 32.8%). Results: The prevalence of nephrotoxicity with impaired eGFR of > 10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.023 and p = 0.026). During all courses of chemotherapy, the prevalence of nephrotoxicity with impaired eGFR of > 20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m2. Conclusions: The results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.
Immune-related adverse events (irAE) in GU cancer patients receiving immune checkpoint inhibitors.
Authors: Zang Peter , Drakaki Alexandra , Faiena Izak , Chan Betty , Tsao-Wei Denice , Groshen Susan G. , Quinn David I. , Dorff Tanya B. 
Published: February 2018

422 Background: Immune checkpoint inhibitors (ICI), particularly PD-1 and PD-L1 antibodies, prolong survival in advanced renal cell (RCC) and urothelial cancer (UC) patients. However, they can cause a variety of serious irAE. We assessed frequency and onset of irAE at experienced centers, and evaluated whether baseline characteristics were associated with irAE. Methods: Pharmacy and clinic schedules identified RCC and UC patients treated with ICI at USC Norris (n = 51) and UCLA (n = 26) from 2014-2016. Prior radiation was defined as completion within 3 months before ICI. Fisher’s exact 2-tailed test was used to evaluate for associations of variables with irAE. Results: 77 patients median age 69 years (49-93) received ICI, 31 with RCC and 46 with UC; 36 received atezolizumab, 29 nivolumab, 9 pembrolizumab, 2 durvalumab, and 1 avelumab. 25 (32.5%) had irAE including pneumonitis (4%), myositis (3%), neurologic event (1%), hepatitis (8%), colitis (1%), rash (8%), endocrinopathy (6%), or hematologic event (1%). 11 (14%) required steroids, 3 (4%) required more intense immunosuppression (infliximab), 1 died of complications from irAE (pneumonitis). 5 were rechallenged with ICI after irAE resolution. Median time to onset of irAEs was 15 weeks; earliest onset of irAE (non-dermatologic) was 3 days after 1st dose, latest onset was 112 weeks. Associations of irAE with variables are listed in the table. Conclusions: irAE were more common in our experience than in published datasets, especially endocrine events, and could occur after the first dose. There was an association between irAE and allergy to antibiotics as well as external beam radiation therapy (EBRT) within 3 months before ICI therapy. [Table: see text]
Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) in patients (pts) with impaired renal function.
Authors: Koshkin Vadim S. , Barata Pedro C. , Zahoor Haris , Rybicki Lisa A. , Almassi Nima , Redden Alicia M , Fergany Amr Farouk , Kaouk Jihad , Haber Georges-Pascal , Stephenson Andrew J. , Martin Allison , Allman Kimberly D , Beach Jennifer , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Grivas Petros 
Published: February 2018

446 Background: Cisplatin-based NAC followed by radical cystectomy is the standard of care in MIBC but many pts are cisplatin-unfit. Data in pts with low glomerular filtration rate (GFR) who receive cisplatin-based NAC is limited. Methods: A retrospective analysis of pts who received cisplatin-based NAC at Cleveland Clinic (2005-2016) was conducted. Pts with pre-NAC GFR < 60 ml/min by either CG or MDRD formula (low GFR; N = 30) were compared to pts with GFR ≥60 (normal GFR; N = 94) in terms of NAC tolerability and outcomes including pathologic complete (pCR, pT0N0) and partial response (pPR, < pT2N0). A secondary analysis compared 3 groups of pts: GFR < 50ml/min (N = 10), GFR 50-59 ml/min (N = 20), and GFR ≥60 (N = 94). Results: Low GFR pts were older (median age 71 vs 65, p < 0.001) and had higher rates of hydronephrosis (33% vs 15%, p = 0.03). ECOG PS, other demographic and TURBT features (stage, LVI, CIS) did not differ significantly. Low GFR pts were more likely to receive gemcitabine/cisplatin (83% vs 71%, p = 0.04) and get split-dose cisplatin (38% vs 16%, p = 0.02). Split-dose cisplatin use in low GFR pts did not impact NAC tolerability or outcomes. NAC cycles completed (median 3 per group) were comparable, and most low GFR pts (70%) completed intended NAC regimen. Low GFR pts were more likely to have early NAC discontinuation (30% vs 13%, p = 0.03) and NAC modification (delay, dose reduction, discontinuation) (66% vs 40%, p = 0.02). No differences were seen in cystectomy completion rate (93% per group), time to cystectomy, length of stay, surgical complications, and GFR change from baseline. Combined pCR/pPR was higher in normal GFR group (54% vs 25%, p = 0.01). Among pts with very low GFR ( < 50 ml/min), 60% completed intended NAC regimen and 70% had NAC modification. Rates of pCR and pPR were low: 0% and 12%, respectively. Conclusions: Low GFR pts were older, had more NAC discontinuations/modifications and lower pCR/pPR rate, but most completed planned NAC cycles. Relative to normal GFR pts, low GFR pts were not prevented or delayed in getting cystectomy, and had comparable impact of NAC on GFR. For carefully selected pts with GFR < 60 ml/min, cisplatin-based NAC is a treatment option, consistent with prior data.
Nomogram-based risk prediction of local and distant relapse after radical cystectomy, and role of perioperative chemotherapy, in patients with muscle-invasive bladder cancer (MIBC): A multicenter study.
Authors: Necchi Andrea , Pond Gregory Russell , Plimack Elizabeth R. , Niegisch Guenter , Yu Evan Y. , Pal Sumanta K. , Bamias Aristotelis , Agarwal Neeraj , Alva Ajjai Shivaram , Srinivas Sandy , Crabb Simon J. , Vaishampayan Ulka N. , Bowles Daniel W. , Berthold Dominik R. , Theodore Christine , Sridhar Srikala S. , Powles Thomas , Rosenberg Jonathan E. , Bellmunt Joaquim , Galsky Matt D. ,   Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)
Published: February 2018

448 Background: Neoadjuvant and adjuvant chemotherapy improve relapse-free survival (RFS) and overall survival of patients (pts) with MIBC. Limited information is available regarding risk prediction of local (RL) vs. distant relapse (RD), including role of perioperative chemotherapy (POC), added to radical cystectomy (Cy). Methods: Data from 1,559 pts, treated at 29 centers from the U.S., Europe, Israel, and Canada, were collected. Pts received Cy for MIBC from 02/90 to 12/13. Of these pts, 782 (50.2%) received POC and Cy, 777 (49.8%) Cy alone. RL and RD were defined as follows: pelvic lymph-nodes/soft tissue only and any extra-pelvic recurrences, respectively. Cumulative incidence methods were used to estimate time-to-(TT) RL/RD, which accounts for the competing risk of other types of relapse. Univariable and multivariable (MVA) Cox regression analyses were performed from the complete-case dataset (n = 1,082). Risk groups were defined according to the number of adverse factors, with corresponding nomogram-based RL and RD risk estimation. All tests were two-sided and statistical significance was defined as a p-value of 0.05 or less. Results: A total of 830 pts (55%) developed a relapse, 447 in the Cy group and 383 in the Cy+POC group. On MVA, POC administration was associated with longer TTRL (p < 0.001) and TTRD (p < 0.001). Other factors associated with RL: histology (non-UC, odds ratio [OR] = 1.47, 95%CI: 1.07-2.01, p = 0.022), pT-stage (p < 0.001), pN-stage (p = 0.038), surgical margins (p < 0.001). For RD: Charlson score (p = 0.006), pT-stage (p < 0.001), pN-stage (p < 0.001). The c-index of the model for RL was 0.685 (95% bootstrapped CI: 0.664-0.718), and for RD was 0.684 (0.655-0.721). Three risk group categories were obtained for both endpoints (0, 1-2, and > 2 risk factors). Results were confirmed after applying 90-day or 180-day landmark analyses, pending external validation. Conclusions: In the largest study that separately analyzed RL and RD risk, we were able to provide risk tools that may be used to optimize locoregional treatments and compare POC benchmark with new drugs in the perioperative setting.
Immunological correlates of response to immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts).
Authors: Tzeng Alice , Diaz-Montero C. Marcela , Rayman Patricia A. , Kim Jin Sub , Pavicic Paul G , Finke James , Barata Pedro C. , Lamenza Marcelo , Devonshire Sarah , Schach Kim , Emamekhoo Hamid , Ernstoff Marc S. , Hoimes Christopher J. , Rini Brian I. , Garcia Jorge A. , Gilligan Timothy D. , Ornstein Moshe Chaim , Grivas Petros 
Published: February 2018

454 Background: Identification of biomarkers predictive of response to ICI could help guide treatment (tx) decisions. We assessed the correlation between PD1/PDL1 expression in key immunomodulatory subsets (myeloid-derived suppressor cells [MDSC]; CD8+ T cells) and tx response in mUC pts treated with ICI. Methods: Serial peripheral blood samples were collected from mUC pts treated with ICI. Flow cytometry was used to quantify PD1/PDL1 expression in MDSC (CD33+HLADR−) and CD8+ T cells (CD8+CD4−) from live peripheral blood mononuclear cells. MDSC were subdivided into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14− CD15+), and immature (I)-MDSC (CD14− CD15−). Mixed-model regression and Wilcoxon rank-sum tests were performed to assess post-ICI changes in immune marker expression and identify correlations between PD1/PDL1 expression and best overall response (BOR) to ICI. Results: Of 36 ICI-treated pts with ≥2 blood samples, 24 received anti-PDL1 (22 atezolizumab/2 avelumab; [A]) and 12 received anti-PD1 (pembrolizumab [P]). 78% were men, median age 69 (46–81), 28% never smokers, 19% had prior intravesical BCG, 39% prior neoadjuvant chemotherapy, and 64% prior cystectomy. BOR to ICI included 3 PR/14 SD/7 PD (A) and 1 CR/2 PR/6 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC (mean change −5.26/dose; p = 0.009), while those of P correlated with decreased %PD1+ M- and I- MDSC (mean change −1.55 and −1.14/dose; p = 0.04 and 0.02, respectively). Though pre-tx %PD1+ CD8+ T cells did not predict BOR, greater PD1 expression by CD8+ T cells within 12 weeks after ICI initiation correlated with BOR (Table). Conclusions: ICI tx correlated with distinct changes in PD1/PDL1 expression by specific peripheral immune cell subsets. Responders to ICI had higher % of PD1+ CD8+ T cells after ICI than non-responders, though pre-tx % were comparable between groups. Further validation of these and other potential blood/tissue biomarkers is ongoing. [Table: see text]
Antitumor effect of cationic liposome incorporating keto-mycolic acid from Mycobacterium bovis bacillus Calmette-Guérin in mouse model.
Authors: Yoshino Takayuki , Miyazaki Jun , Kojima Takahiro , Kandori Shuya , Akaza Hideyuki , Yano Ikuya , Nishiyama Hiroyuki 
Published: February 2018

461 Background: Intravesical instillation of live bacillus Calmette-Guérin (BCG) is an established immunotherapy for non-muscle invasive bladder cancer. However, development of non-infectious agents has been expected, because there are several problems due to instillation of live bacteria. BCG cell wall skeleton is known to stimulate host immune system, but the mechanism is still unknown. Mycolic acid (MA), which consist of three subclasses (α, keto, methoxy), is the most abundant lipid component of BCG cell wall and is expected to be one of essential active components. Objective: In order to identify active component from BCG cell wall and develop non-infectious BCG-derived immunotherapy, anti-tumor activities of cationic liposomes incorporating each subclass of MA were assessed using mouse syngeneic graft model. Methods: Heat killed packed cells of M. bovis BCG Tokyo 172 were fully hydrolyzed and MA was obtained. MA was separated to three subclasses by thin layer chromatography. Cationic and hydrophilic liposomes incorporating each subclass of MA were prepared. C57BL/6 mice were subcutaneously inoculated with a mixture of　MB49 cells and PBS or liposome with/without MA followed by additional injection of PBS or liposome. Tumor growth was monitored. Infiltration of CD4/8 lymphocytes was examined by immunostaining. Results: Cationic liposomes were internalized into cytoplasm of MB49 cells, a mouse bladder cancer cell line. Cell proliferation was not affected by liposome incorporating MA. Tumor growth was significantly suppressed in mice treated with keto MA-liposome (vs PBS, p = 0.007), but not in mice treated withα-or methoxy-MA liposomes. Number of infiltrating CD8 lymphocytes was higher in tumor treated with keto MA-liposome than control. Antitumor effect of keto MA-liposome disappeared in nude mouse, while the effect existed in beige mouse with NK activity deficiency (vs PBS, p = 0.045). Conclusions: Keto MA-liposome showed the strongest antitumor effects in mouse model among three subclasses. T cell immunity may contribute to those effects.