bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcome of bacilles Calmette-Guerin perfusion therapy for upper urinary tract urothelial carcinoma in situ.
Authors: Yoneyama Takahiro , Sugiyama Naoki , Suzuki Yuuichirou , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

265 Background: Bacillus Calmette-Guerin (BCG) therapy has already been established as a treatment for muscle noninvasive bladder cancer. Although there are several reports indicating the effectiveness of BCG perfusion therapy for the upper urinary tract urothelial carcinoma in situ (CIS), it is not well established yet. We conducted a retrospective study to assess the long-term outcome of BCG perfusion therapy for the upper urinary tract CIS. Methods: Twenty-six subjects (20 male, 6 female) who received BCG perfusion therapy for the upper urinary tract CIS from December 1997 to December 2011 were enrolled. Ten subjects had the entire urinary tract CIS, seven had bilateral, nine had unilateral CIS of the urinary tract. The average period of observation was 52.6 months (ranging from 5 to 156 months), and the average subject age was 73.6 years (ranging from 56 to 90 years). We used a double-J catheter for 17 cases, a transvesical single-J catheter whose curl was positions in an upper calyx for eight cases, and a straight ureteral catheter inserted for ureterocutaneostomy for one case. We used 80 mg of BCG for the first five cases, 40 mg for the late twenty-one cases. Urine cytology was performed to assess the treatment validity. Results: Of the 26 cases, the treatment protocol was completed in 21 cases. Urine cytology tests became negative in 22 of the 26 subjects (84.6%) who underwent upper urinary tract perfusion. Among these 22 subjects who had negative tests, five subjects had a recurrence in their upper urinary tracts. Side effects were observed in 25 subjects (96.5%), and the most common side effect was bladder irritation. Localized renal tuberculosis which was successfully treated with conservative therapy was seen in two cases. Conclusions: BCG perfusion therapy for the upper urinary tract CIS is active. However, severe side effects are possible, and careful observation is essential while using this therapy.
Proportion of elderly patients with advanced bladder cancer receiving cisplatin-based chemotherapy: A large Medicare database study.
Authors: Chen Guoqing J. , Galsky Matt D. , Latini David M. , Sonpavde Guru 
Published: February 2017

276 Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use and pattern of chemotherapy in Medicare fee-for-service elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4b, N0, M0; Any T, N1–N3, M0; Any T, Any N, M1) between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between receiving chemotherapy and patient demographics, and clinical characteristics. Results: A total of 1,031 Medicare FFS elderly patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 40.1% were T4bN0M0, 55.3% were any N1-3M0 and 4.6% were any T, any N, M1. Overall use of chemotherapy occurred in 51.6% of the study patients. Of these patients receiving chemotherapy, carboplatin accounted for 50.6% in the initial treatment, followed by cisplatin in 39.7% and other agents in 9.8%. 37.5% of patients received chemotherapy within 6 months, 14.1% after 6 months, and 48.4% had not receive any chemotherapy over the study period. There were no statistical differences according to gender, race, and age. There were variations in receiving chemotherapy by stage: T4bN0M0 (51%), any T, N1-3, M0 (52.3%) or any T, any N, MI (48.9%), p<0.05. Conclusions: Among elderly patients presenting with ABC in the SEER-Medicare linked database, only 51.6% received chemotherapy and of these only 39.7% received cisplatin. Drug development for this population should focus on chemotherapy-ineligible and cisplatin-ineligible patients. Further analysis will explore practice patterns in prescribing chemo regiments in the initial treatment of ABC and its impacts on patient outcomes.
Radiologic response (RR) by MRI in patients (pts) with muscle-invasive urothelial cancer (MIUC) undergoing neoadjuvant chemotherapy.
Authors: Qu Angela Q. , Choueiri Toni K. , Jacobus Susanna J. , Rosenberg Jonathan E. , Ramaiya Nikhil H. , Krajewski Katherine Maragaret 
Published: February 2017

283 Background: Standard response criteria do not always provide a meaningful assessment of treatment benefit in pts with MIUC. We examined the utility of contrast-enhanced imaging in predicting disease free survival (DFS) in MIUC pts, and its correlation with pathological downstaging on radical cystectomy (RC) specimen. Methods: Baseline and post chemotherapy imaging, primarily gadolinium-enhanced pelvic MRI, from pts enrolled on a phase II prospective study of neoadjuvant cisplatin-based chemotherapy were reviewed by 2 oncoradiologists (NR, KK). DFS was defined as time from RC to evidence of disease progression or death. Qualitative (QL) RR was defined by at least moderate decrease in the primary tumor and lymph nodes after chemotherapy, with visually decreased primary tumor bulk by at least half, normalization of node size, and delayed enhancement of residual tumor and nodes. Quantitative (QN) RR was assessed according to anatomic TNM downstaging per AJCC staging criteria 7.0. Fisher’s exact test was used to compare RR with pathological dowstaging. DFS distributions within RR subgroups were estimated with the Kaplan-Meier method and compared using the logrank test. Results: All 39 pts from the original study were included in this analysis. At baseline, 42% of pts had cT2 disease, 42% had cT3, 16% had cT4, and 45% had N1 disease. 91% of pts had bladder primary, and 84% of pts were assessed by MRI. Results showed QL RR in 64% (90% CI 50-77) of pts, QN RR in 61% (90% CI 47-75), and ≤pT1N0M0 in 49% (90% CI 35-63). While there was no association between pathological downstaging and QN RR, there was a modest association with QL RR (p=0.096). 60% of pts with QL RR achieved ≤pT1N0M0 and 71% of pts without QL RR were >pT2. QL RR was also a strong predictor of DFS with an 18-month DFS advantage of 83% (95% CI 56-94) among responders vs. 32% (95% CI 6-63) in non-responders (p=0.036). Conclusions: QL RR post neoadjuvant therapy is modestly associated with pathological downstaging in pts with MIUC and strongly predictive of DFS. Results suggest post-chemotherapy, pre-operative imaging may be a valuable prognostic tool. Confirmation in other UC populations and treatment settings should be explored.
A study of genes and microRNAs that may predict clinical responses to anti-CTLA-4 therapy.
Authors: Gao Jianjun , Chen Hong , Ng Tang Derek , Sharma Padmanee 
Published: February 2017

285 Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, Ipilimumab (BMS), has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of Ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+ T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved Phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of Ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+ T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Ipilimumab treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, Ipilimumab significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that Ipilimumab induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Ipilimumab treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.
Association of persistent, unexplained leukocytosis, a paraneoplastic syndrome, with poor prognosis in patients with urothelial carcinoma of the bladder.
Authors: Izard Jason Patrick , Gore John L. , Yu Evan Y. 
Published: February 2017

291 Background: Unexplained leukocytosis, thought to be associated with paraneoplastic GCSF, has been described in several malignancies and is linked to a poor prognosis. We sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated WBC. Methods: We queried a prospectively maintained database at the University of Washington. Patients were included if they had a histological diagnosis of urothelial carcinoma of the bladder and a WBC of >20 x 103cells/µl. Patient charts were reviewed and were excluded from analysis if the leukocytosis was not persistent in duration or if an underlying cause for the leukocystosis could be identified. Clinical, histological and laboratory data were then collected from the remaining patient cohort. Results: We identified a total of 44 patients who met the inclusion criteria of having urothelial carcinoma of the bladder with a WBC of >20 x 103cells/µl. Of these patients, 7 (16%) patients with a median age of 61.9 (range 34 - 80) yrs at diagnosis had persistent, unexplained leukocytosis. Mixed histologies were present in 3 patients (extensive squamous differentiation in 2 and sarcomatoid differentiation in 1). At the time of presentation with leukocytosis, 5 of 7 had muscle invasive disease and 3 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n = 5), thrombocytosis (n = 5) and anemia (n = 6). All patients died from their disease with the exception of one who is currently alive with locally advanced and unresectable disease 8 months after presentation. Median time from leukocytosis until death was 55 (range 8 - 139) days. Chemotherapy was able to achieve a WBC response in 2 of 4 patients although neither demonstrated a substantial reduction in tumor volume. Both patients ultimately developed a recurrence of their leukocytosis after chemotherapy and progression of their disease. Conclusions: The presence of leukocytosis conveys a poor prognosis. To our knowledge this represents the largest case series of patients with paraneoplastic leukocytosis secondary to urothelial carcinoma.
CEP-11981, a small molecule inhibitor of multiple angiogenic targets, in a preclinical system of urothelial carcinoma (UC).
Authors: Jian Weiguo , Levitt Jonathan M. , Lerner Seth P. , Sonpavde Guru 
Published: February 2017

293 Background: The systemic therapy of advanced UC has significant unmet needs. Angiogenesis appears to play a major tumorigenic role in UC, and inhibitors of the VEGF axis have demonstrated activity in clinical trials. Ang/Tie2 and FGFR1 are angiogenic pathways that may collaborate with the VEGF pathway to promote growth. Hence, we sought to examine the preclinical activity of CEP-11981, a small molecule inhibitor of Ang/Tie2, FGFR1 and VEGFR-1-2, in UC. Methods: The in vitro anti-tumor activity of CEP-11981 was evaluated in 4 human cell-lines (5637, TCC-SUP, RT4, RT112). In vivo examination of the anti-tumor activity of different doses of daily oral CEP-11981 for up to 4 weeks was examined in subcutaneous RT4 xenografts. Harvested xenograft tumors were subjected to immunohistochemistry (IHC) to evaluate apoptosis (cleaved-caspase [cc]-3) and angiogenesis (CD31). Results: In vitro activity was not detected at low micromolar concentrations in all 4 cell-lines (attainable in human subjects). Preliminary experiments suggested that both 5 mg/kg and 10 mg/kg orally once daily induced similar regressions of RT4 xenografts, which appeared greater than regressions with 2.5 mg/kg orally once daily. Given that the weight of mice was better maintained with 5 mg/kg dose, we performed the confirmatory experiment comparing placebo with CEP-11981 at 5 mg/kg orally once daily in RT4 xenografts. At this dose, CEP-11981 significantly arrested the growth of UC xenografts compared to control (p<0.05). IHC of harvested RT4 xenografts demonstrated numerically lower angiogenesis (p=not statistically significant) but no change in cc-3. Modulation of Tie2 is being examined. Conclusions: CEP-11981 demonstrated significant preclinical cytostatic anti-tumor activity against human UC xenografts in a murine model, which was attributable to inhibition of angiogenesis. Clinical development of CEP-11981 in tolerable combination regimens and the discovery of tumor and host related biomarkers predictive for benefit are warranted.
Real-world experience with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel (D): Data from PROCEED.
Authors: Sartor A. Oliver , Cooperberg Matthew R. , Vogelzang Nicholas J. , Scholz Mark Creamer , Concepcion Raoul S. , Berry William R. , Pieczonka Christopher , Dakhil Shaker R. , Vacirca Jeffrey L. , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Higano Celestia S. 
Published: February 2017

30^ Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The phase III IMPACT trial showed a significant improvement in overall survival with sipuleucel-T treatment (tmt). In IMPACT, D use was prohibited within 3 months prior to registration due to the potential immunosuppressive impact of chemotherapy. PROCEED is an ongoing, multicenter, phase 4 registry enrolling pts receiving sipuleucel-T in the real-world setting. Enrollment has no restrictions on D use; thus, data from PROCEED may help determine whether prior D affects sipuleucel-T manufacture. Here we present preliminary results on baseline demographics and product parameters in PROCEED subjects with and without prior D exposure. Methods: Pts who were treated with sipuleucel-T within the prior 6-months at clinical sites were asked to provide informed consent to participate in PROCEED. Results: By September 2012, 560 pts completed sipuleucel-T tmt; 15% previously received D (median 291 days prior to 1st sipuleucel-T infusion). Patients with prior D had higher PSA levels, and those with recent D use tended to have a lower performance status and higher Gleason scores, but product parameters were generally comparable between the groups (see table). Conclusions: Pts enrolled in PROCEED with and without prior D exposure had different baseline demographics and disease characteristics. However, sipuleucel-T product parameters were comparable regardless of prior D exposure. Clinical trial information: NCT01306890. [Table: see text]
Impact of baseline prognostic factors on progression-free survival at 6 months (PFS6) and response in patients receiving second-line therapy for advanced urothelial carcinoma (UC).
Authors: Pond Gregory Russell , Agarwal Neeraj , Bellmunt Joaquim , Choueiri Toni K. , Qu Angela Q. , Fougeray Ronan , Niegisch Guenter , Galsky Matt D. , Wong Yu-Ning , Stadler Walter Michael , Sridhar Srikala S. , Sternberg Cora N. , Sonpavde Guru 
Published: February 2017

301 Background: PFS6 was identified to be a robust intermediate endpoint in the setting of second-line therapy for advanced UC (Sonpavde, ESMO Congress, 2012) We studied the impact of second-line prognostic factors (Sonpavde, ESMO Congress 2012) (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and response rate (RR) to enable comparison of outcomes across phase II trials. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. Results: Data regarding progression, Hb, LM, PS and TFPC were available in 570 patients, who were considered evaluable. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was <6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). PFS6 and RR varied significantly according to risk group (Table). For every unit increase in risk group, the hazard of progression in 6 mo increased by 41% and the odds of response decreased by 48%. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. These data facilitate comparison of outcomes across phase II trials enrolling heterogeneous populations. [Table: see text]
Combining next-gen sequencing of TP53 and FGFR3 for detecting bladder cancer-related mutations.
Authors: Millholland John M. , Campo Maria F. , Fernandez Cecilia A. , Shuber Anthony P. 
Published: February 2017

304 Background: We have recently described an ultra-deep amplicon sequencing method for FGFR3 in urine that closely replicates the sensitivity found in tissue. While FGFR3 mutations are present in a large fraction of non-invasive tumors, these mutations are rarely detected in invasive bladder tumors. To complement our existing FGFR3 deep sequencing assay, we have developed a sequencing assay for TP53. Mutations in TP53 are commonly found in advanced bladder cancer, and show little overlap with FGFR3 mutations. This proof of concept study demonstrates detection of FGFR3 and TP53 in bladder cancer tissue. Methods: The FGFR3 sequencing assay was performed as described previously, permitting the detection of 9 mutations associated with bladder cancer. Similarly, amplicons were designed against TP53 exons 5-8 using, permitting the detection of 133 unique TP53 mutations previously detected in bladder cancer. Primary amplification was performed on DNA isolated from 3 10µ tissue sections. The resulting PCR products were used as template for emulsion PCR and sequenced using the Ion Torrent PGM. Samples were analyzed for total DNA reads and number of mutant sequencing reads to determine percent mutation. Results: Previously we analyzed 151 non-invasive bladder tumor samples for the presence of FGFR3 mutations. Of these samples, 93 out of 151 (61.5%) were positive for FGFR3 mutations. An additional set of 10 high stage bladder tumor samples were analyzed for mutations in TP53. Of these samples, 5 out of 10 (50.0%) were positive for TP53 mutations, while a separate sample was found to be positive for FGFR3 only. Importantly, a TP53 mutation was detected in a Tis carcinoma in situ sample. These studies will be expanded to a larger set of bladder cancer tissues and urine samples to more accurately assess clinical performance of this FGFR3/TP53 deep sequencing assay. Conclusions: We have developed a multiplexed FGFR3 and TP53 sequencing assay that can detect mutations in a broad range of bladder cancer stages. The complementarity of mutations found in these two genes may allow for the detection of a larger fraction of patients with undiagnosed bladder cancer.
DNA repair capacity and tumor recurrence in patients with non-muscle-invasive bladder cancer (NMIBC).
Authors: Donahue Timothy F. , Donat S. Machele , Patel Himali , Chou Joanne F. , Bayuga Sharon , Olson Sara H. , Zerillo Jessica Ann , Dominguez Gemma , Leoce Nicole M. , Herr Harry W. , Orlow Irene 
Published: February 2017

305 Background: NMIBC requires lifelong surveillance to monitor for recurrence. Identifying patients at greatest risk and altering surveillance accordingly could impact health care cost. Inadequate DNA repair may increase the risk for developing subsequent tumors. This prospective study evaluated the association between DNA damage/repair capacity and tumor recurrence with the goal of finding new prognostic markers. Methods: Patients newly diagnosed with NMIBC (n=100) who received standard care provided blood samples and completed risk surveys and were followed for a median of 78 mos. DNA damage in peripheral blood lymphocytes measured with the Comet Assay revealed constitutive damage, sensitivity to carcinogens after exposing cells to the tobacco-derived carcinogen BPDE, and repair capacity after allowing cells to repair post BPDE induced damage. DNA damage was expressed as log-transformed Tail Intensity. Median time to recurrence and cumulative incidence of recurrence at 4 mos were estimated by Kaplan-Meier methods and compared by log-rank test. Hazard ratios for recurrence in association with patient characteristics and DNA damage/repair variables were estimated with Cox proportional hazard models. Associations of DNA damage/repair variables between patients’ characteristics were tested with Wilcoxon Rank-Sum. Results: This NMIBC cohort included patients with mean age 64 yrs and 71% males. Tumors were high grade in 74% and multifocal in 34%. Median time to recurrence was 6 months and 42/69 recurrences occurred <4 mos. Patients with higher grade/stage, multifocality, and intravesical therapy had higher cumulative incidence of recurrence at 4 mos (p<0.01). Those with higher stage/grade compared to low stage/grade tumors showed significant reduction in DNA repair capacity after exposure to BPDE (p<0.03). Conclusions: In univariate analysis, DNA damage is associated with higher stage and higher grade tumors; however host DNA damage/repair capacity does not predict recurrence in NMIBC. Traditional disease characteristics including multifocality, high-grade, increasing stage, and intravesical therapy remained predictors of recurrence.