bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophagy inhibition (AI) as a novel treatment strategy in bladder cancer (BC).
Authors: Grivas Petros , Visconte Valeria , Day Mark L. , Day Kathleen C. , Liebert Monica , Palmbos Phillip Lee , Tomlins Scott A. , Carew Jennifer 
Published: February 2017

449 Background: BC response to chemotherapy has reached a plateau; novel treatment targets are needed. Autophagy is an important protein degradation mechanism that may be involved in chemotherapy response/resistance. AI was shown to overcome drug resistance in preclinical studies, but has not been well studied in BC. We conducted comprehensive gene expression analysis in BC cell lines to define their autophagy pathway expression signatures. We then investigated the anti-tumor activity and pharmacodynamics (PD) of our novel autophagy inhibitor ROC-325 (superior to hydroxychloroquine) in preclinical BC models with high baseline autophagy levels. Methods: Baseline expression of autophagy-related genes was evaluated by RNASeq in 21 BC cell lines. Gene and protein expression of selected autophagy-related genes was confirmed by qRT-PCR and immunoblot. PD effects of ROC-325 on lysosomal protease cathepsin D (CTSD) were assessed in 2 selected BC cell lines: UM-UC-3 (mesenchymal), UM-UC-6 (epithelial). The ability of ROC-325 (72 hour treatment) to augment gemcitabine (G) and cisplatin (C) activity in the 2 cell lines was evaluated by MTT assay and combination index analyses, t- test with 2-sided comparison was used, experiments were in triplicate. Results: RNASeq showed significant heterogeneity in baseline expression of early and late autophagy-related genes among BC cell lines; elevated expression of multiple autophagy-related genes was a prevalent phenomenon. CTSD level was elevated in multiple cell lines. PD analysis showed dose-dependent increase of CTSD expression in UM-UC-3 cells after ROC-325 (1-10uM) treatment correlating with reduced cell viability. The activity of G and C was greater in UM-UC-6 vs UM-UC-3 cells. Both cell lines were sensitive to ROC-325. The addition of ROC-325 to G or C yielded additive benefit in both cell lines. In UM-UC-6, ROC-325 addition significantly increased the activity of GC combination vs GC alone (p = 0.0049). Conclusions: AI merits further investigation as new treatment strategy in BC. Evaluation of in vitro and in vivo efficacy/safety of ROC-325 with/without other agents, and assessment of putative predictive biomarkers is being pursued in BC models with genomic and transcriptomic annotation.
Urachal versus nonurachal adenocarcinomas of the bladder: A population-based report.
Authors: Sun Maxine , de Velasco Guillermo , Meyer Christian P , Bellmunt Joaquim , Nguyen Paul L. , Trinh Quoc-Dien , Choueiri Toni K. 
Published: February 2017

450 Background: Previous studies are inconclusive on whether urachal vs. non-urachal adenocarcinomas of the urinary bladder have different prognoses. Our objective was to assess survival differences between urachal vs. non-urachal adenocarcinomas in light of evolving treatment strategies over the past years. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with a diagnosis of adenocarcinoma of the urinary bladder between years 1988 and 2012. The variable of interest was urachal vs. non-urachal adenocarcinomas. Kaplan-Meier curves and log-rank tests were performed to assess the univariable effect of urachal vs. non-urachal adenocarcinomas on survival. Multivariable Cox regression analyses were performed for prediction of cancer-specific mortality (CSM) and overall mortality. Sub-analyses comprised of competing-risks regression models. Results: Overall, 2345 (89%) and 301 (11%) non-urachal and urachal adenocarcinoma patients were identified, respectively. The 5-year CSM-free survival rates for urachal vs. non-urachal adenocarcinomas were 63% vs. 50% (P< 0.001). For the same groups, the 5-year overall survival rates were 50% vs. 32%, respectively (P< 0.001). In multivariable Cox regression analyses, no difference was recorded between urachal vs. non-urachal adenocarcinomas for CSM (hazard ratio [HR]: 0.86, P= 0.2) or any mortality (HR: 0.84, P= 0.07). Important prognosticators of CSM and survival were surgery, lymph node dissection, disease stage and grade. Conclusions: No survival difference was recorded in the current study between urachal vs. non-urachal adenocarcinoma of the bladder. However, surgery and lymph node dissection constitute important factors for both tumor types.
Renal function in bladder cancer patients after trimodality therapy: Long-term results of a large institutional experience.
Authors: Roberts Hannah J. , Drumm Michael , Niemierko Andrzej , Goldberg Saveli , Clayman Rebecca Helen , Heney Niall M. , Feldman Adam S. , Wszolek Matthew F , Michaelson M Dror , Lee Richard J. , Saylor Philip James , Zietman Anthony L. , Shipley William U. , Efstathiou Jason A. 
Published: February 2017

453 Background: Maintenance of renal function following treatment of bladder cancer presents an ongoing challenge. The decline following radical cystectomy is well documented. However, in patients undergoing trimodality bladder-sparing therapy consisting of transurethral resection (TURBT) and concurrent chemoradiation followed by adjuvant chemotherapy, renal function is poorly understood. Methods: We performed a retrospective review of 178 patients with muscle-invasive bladder cancer who underwent bladder-sparing therapy between 2001 and 2013 and collected nadir creatinine values in the month preceding TURBT and at 1, 3, 5, 7, and 9 years post treatment initiation. Wilcoxon signed-rank test and mixed effects analysis were performed to compare the pre-treatment and post-treatment levels of creatinine and EGFR and to analyze their temporal change. Results: Median follow-up was 48 months (range: 1 to 162 months). The mean pre-treatment creatinine and EGFR were 1.12 mg/dl and 71 mg/dl, respectively. Cr increased to 1.21 mg/dl and EGFR decreased to 65 mg/dl at 1 year following treatment initiation (p = 0.001, p = 0.002). All post-treatment values were also significantly different from pre-treatment values (all p values < 0.002), but there was no significant difference between the post-treatment values over time. Conclusions: Following bladder-sparing therapy for muscle invasive bladder cancer, renal function was generally well preserved in the long term. Although there was a modest yet statistically significant decrease in renal function that occurred during the first year, there was no further decline up to 9 years. While this initial decrease in function is of unknown clinical significance, the lack of further decline after 1 year is different from similar studies following cystectomy.
Amplification of chromosome 3q21-25 in urothelial carcinoma with squamous differentiation.
Authors: Sanford Thomas , Meng Maxwell V. , Porten Sima P. 
Published: February 2017

457 Background: Squamous differentiation is found in up to 60% of patients with urothelial carcinoma of the bladder. There is conflicting evidence regarding clinical relevance of aberrant urothelial differentiation as both population-based and retrospective studies have supported and refuted its correlation with poor prognosis and advanced stage in multivariate models. The biology of these tumors is poorly understood but some suggest that extensive squamous differentiation may resemble pure squamous tumors with similar responses to chemotherapy, radiation, and higher rate of local recurrence. Our aim was to compare tumors with squamous differentiation with those of pure urothelial histology at the genomic level to better elucidate targetable differences. Methods: We reviewed pathology reports for 412 patients with urothelial carcinoma from TCGA to identify patients with any amount squamous differentiation. Copy number alteration data obtained via the GISTC algorithm was downloaded from cbioportal.com. Chi square analysis was used to compare chromosomal amplifications in samples with squamous differentiation compared with samples that had no amount of variant histology. Results: 50 patients (12%) had some squamous differentiation, of which 15 commented on the percent of involvement – on average, 17% of the sample had squamous differentiation. A total of 257 (62%) of patients had no variant histology. Multiple specific sites in the 3q21-26 chromosomal region were noted to be amplified in squamous histology compared with pure urothelial carcinoma. Specific genes found to be amplified included SOX2 and PIK3. Conclusions: Amplifications of chromosome 3q21-25 were enriched in patients with squamous differentiation compared to those with pure urothelial carcinoma of the bladder. Amplification of this region has been reported in squamous transformation in multiple sites, including lung cancer. This study shows that, similar to other cancers, SOX2 may be necessary for squamous transformation. Furthermore, squamous cancer, which has traditionally though to be chemo-resistant, may respond to agents that target amplifications of genes found on the long arm of chromosome 3 including the PIK3-Akt pathway.
Characterization of mutational load in patients with advanced urothelial cancer.
Authors: Pal Sumanta K. , Ali Siraj Mahamed , Ennis Riley , Elvin Julia Andrea , Vergilio JoAnn , Suh James , Yelensky Roman , Ross Jeffrey S. , Miller Vincent A. , Joshi Monika , Choueiri Toni K. , Stephens Philip J. , Frampton Garrett Michael 
Published: February 2017

460 Background: The efficacy of novel immunotherapeutic agents (e.g., PD-1/PD-L1 and CTLA4 inhibitors) in advanced cancer is linked to tumor mutational load. We assessed mutational load via comprehensive genomic profiling (CGP) performed in the course of clinical care for patients with advanced urothelial cancer (UC). Methods: DNA was extracted from 40 microns of FFPE sections from 760 consecutive patients with relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for at least 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Mutational load was characterized as the number of such SUBs or INDELs per megabase (Mb) after filtering to remove known somatic and deleterious mutations, given that these are selected for with hybrid capture. Results: The median age of the patients was 66 years old with a 3:1 male:female ratio. Mean mutations per megabase were assessed as a range of 0 to 79, and the 25th, median, and 75th quartile thresholds were 3.2, 5.5, and 8.8. MSH6 alterations in 0.8% cases had a median of 15.2 mutations per megabase. However, the ten most frequently altered genes in this series- TERT (64%), TP53 (54%), CDKN2A (35%), CDKN2B (28%), KDM6A (24%), ARID1A (23%), MLL2 (22%), PIK3CA (21%), RB1 (21%) and FGFR3 (19%) - were not associated with differences in mutational load. Conclusions: A highly variable mutational load was seen in patients with advanced UC. A subpopulation of MSH6-altered UC had very high mutational loads relative to other UCs. Further correlation to clinical outcomes will be investigated to assess the correlation between mutational load and response to immunotherapy.
Latent class analysis of bladder urothelial carcinoma to reveal sub-classes defined by alterations to chromatin and signal transduction networks.
Authors: Fichtenholtz Alex , Khan Alyna , Ross Jeffrey S. , Ali Siraj Mahamed , Miller Vincent A. , Stephens Philip J , Neumann Eric 
Published: February 2017

469 Background: 70,000 new cases of bladder urothelial carcinoma are diagnosed in the United States each year. Previous studies of this disease suggest two divergent pathways of carcinogenesis, with ~70% of cases being driven by alterations in signal transduction pathways (FGFR3, HRAS) and the remainder featuring alterations in cell cycle genes (TP53, RB1). Other studies focus on the high prevalence of alterations in chromatin remodeling genes (ARID1A, CREBBP, EP300) in this tumor type. The relationship between chromatin modifier alterations and the two bladder TCC sub-classes is not yet understood. Methods: Comprehensive genomic profiling (CGP) on 638 clinically confirmed cases of advanced bladder urothelial carcinoma was performed using the FoundationOne platform. The coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer were sequenced and analyzed for base substitutions, insertions, deletions, copy number alterations and select gene fusions. The resultant alteration profiles were analyzed for their information content with an entropy-based approach and the profiles were subjected to hierarchical latent class analysis (LCA). Results: CGP of 488 male and 150 female UCs of median age 66 (min: 29, max: 87) resulted in 3241 detected alterations across 302 unique genes, for a mean of ~5.1 known or likely somatic alterations per sample. The most commonly altered genes were TP53, CDKN2A/B, ARID1A, KDM6A, and MLL2. Information was concentrated in the 33 most frequently altered genes. Multiple high level clusters were defined by combinatorial patterns of alterations in TP53, CDKN2A/B, RB1, and FGFR3. Sub-classes were defined by mutually exclusive alterations in the chromatin modifiers KDM6A, MLL2, and ARID1A. Conclusions: We present a global picture of UC sub-classes that encompasses previously identified local relationships including the mutual exclusivities between FGFR3 and TP53, RB1 and CDKN2A/B, and KDM6A and MLL2. In the context of clinically relevant genomic alterations that auger response to targeted therapies, identification of sub-classes of UC may further delineate response to therapy.
Conditional survival of patients with metastatic testicular germ-cell tumors (MT-GCT) treated with first-line curative therapy.
Authors: Ko Jenny J. , Bernard Brandon David , Tran Ben , Li Haocheng , Asif Tehmina , Stukalin Igor , Lee Margaret , Day Daphne , Alimohamed Nimira S. , Sweeney Christopher , Bedard Philippe L. , Heng Daniel Yick Chin 
Published: February 2017

472 Background: The IGCCCG risk stratification prognosticates survival outcomes in metastatic testicular germ cell tumour (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment (conditional survival) is unknown. We evaluated conditional survival in patients with MT-GCT who were eligible for first-line therapy. Methods: We included patients who were eligible for first-line therapy for MT- GCT at 5 tertiary cancer centres from 1990 to 2012. We assessed 2-year (Y) conditional overall (COS) and disease-free survival (CDFS) at a given timepoint, defined as the probability of surviving, or surviving and disease-free, respectively, for an additional 2Y at a given timepoint since the start of first-line treatment. Outcomes were stratified by IGCCCG risk criteria, pathology and age. Results: For all patients (n = 942, favourable 63%/intermediate 19%/poor 16%), median follow-up was 99 months (m) (IQR 56-141); 2YCOS increased from 92% (95% CI 91%–94%) at baseline to 98% (95% CI 97%–99%) at 24m, and 2Y CDFS increased from 83% (95% CI: 81%-86%) at baseline to 98% (95% CI 97%-99%) at 24m after diagnosis. 2YCOS changed little in the IGCCCG favourable and intermediate groups, but in the poor-risk group, improved from 71% (95% CI 64%–78%) at 0m to 93% (95% CI 89%-98%) at 24m. 2Y CDFS for favourable risk group improved significantly at 12m (91% baseline vs. 95% at 18m); intermediate, at 12m (84% baseline vs. 95% at 12m); poor, at 12 m (55% baseline vs. 85% at 12m). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to > 2Y post therapy. No significant differences in COS and CDFS were noted between seminoma and non-seminoma, while older patients ( > = 40) had inferior 2Y COS from 0-18m but no differences were noted after 18m. Conclusions: Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. A poor-risk patient, after 2Y of survival, had the same probability of relapse and survival as a favourable/intermediate risk patient.
Cyclin-dependent kinase 4/6 inhibition for the treatment of mature teratoma germ cell tumor: Long-term follow-up of a phase II study.
Authors: Narayan Vivek , Hwang Wei-Ting , Lal Priti , Rosen Mark Alan , Gallagher Maryann , O'Dwyer Peter J. , Vaughn David J. 
Published: February 2017

474 Background: We have previously reported the results of a phase II clinical trial evaluating the safety and efficacy of palbociclib for the treatment of patients with unresectable germ cell tumors, including mature teratoma, teratoma with malignant transformation, and non-teratomatous tumors. In an effort to better assess the efficacy of palbociclib, we now report long-term follow-up of a more homogeneous population of patients with unresectable mature teratoma treated on the phase II clinical trial, with an emphasis on clinically-relevant endpoints for this incurable patient population. Methods: This was a retrospective analysis with long-term follow-up of the patient cohort with mature teratoma treated on the phase II study of palbociclib for the treatment of retinoblastoma protein-expressing germ cell tumors. Patient clinical data was obtained from the medical records and from communication with the enrolled patients and referring medical providers. Major medical events for the treatment of germ cell tumor, including before, during, and after study treatment, were recorded. Clinical events of interest included the initiation of systemic therapy, radiation therapy, surgical debulking, or other invasive procedures. Study endpoints included pre-study and post-study clinical event rates, event-free survival, and radiographic progression-free survival. Results: Long-term follow-up was obtained for 12 patients with mature teratoma. The median pre-study follow-up time was 19.7 months, and the median post-study follow-up time was 38.0 months. The median number of palbociclib treatment cycles was 11. The pre-study clinical event rate was 2.27 events/year (95% CI 1.66 – 3.13), and the post-study event rate was 0.62 events/year (95% CI 0.36 – 1.09). The median progression-free survival was 5.3 months (95% CI 1.8 – 22.6), and the median event-free survival was 16.2 months (95% CI 3.0 – 24.3). Conclusions: The initiation of palbociclib resulted in a clinically-meaningful delay in disease-related major clinical events and radiographic progression. These findings lend further support to the therapeutic activity of CDK4/6 inhibition in this incurable patient population.
Quantifying decreased radiation exposure from modern CT scan surveillance programs of germ cell tumors.
Authors: Howard Stephanie Anne Holler , Rosenthal Michael , Qin Lei , Bernard Brandon David , Beard Clair , Sweeney Christopher 
Published: February 2017

478 Background: Active surveillance (AS) is increasingly used to manage clinical stage I testicular cancer (CS1TC,) but has the risk of radiation exposure from CT scans. Modern CT scanners with iterative reconstruction techniques (IRT) produce equivalent image quality with less radiation dose compared with traditional filtered back projection (FBP). Data examining timing of CS1TC relapses on AS have suggested it is safe to decrease CT scanning of abdomen and pelvis from the NCCN 2009 guideline of approximately 16 scans over 5 years to 7 scans. We examine the impact of the CT upgrade and decreased scans on radiation dose and associated risks. Methods: This IRB-approved study enrolled 24 CS1TC patients who had CT scans on the same Toshiba Aquilion 64 CT before and after IRT software installation. Dose-length product and CT dose index volume were recorded. A medical physicist calculated effective doses. Radiation doses were compared using the Wilcoxon signed rank test. Median effective dose per scan was multiplied by scan number based on 16 and 7 scan 5 year AS protocols to calculate an estimated cumulative dose (ECD). Lifetime attributable risk (LAR) of dying of a radiation-associated solid tumor was estimated for a single exposure at age 35 using the excess absolute risk transport model from the Biological Effects of Ionizing Radiation VII analysis of long-term atomic bomb survivors. Results: Median pre and post upgrade doses were 12.5 mSv and 7.7 mSv respectively (p < 0.0001). A linear regression model with a constrained zero intercept fit to the data found that IRT dose was best estimated as 61% of FBP dose (95% CI 0.56 – 0.66). Table 1 lists ECD and LAR data for both AS regimens pre and post upgrade. Conclusions: IRT, as part of an integrated approach to optimize patient outcome, should reduce CT-related risks by about 39%. This reduction, combined with the scan reduction of newer AS regimens, further significantly lowers the already small potential mortality of imaging associated cancers. [Table: see text]
Impact of bleomycin (BLM) administration on the development of pulmonary toxicity in advanced germ cell tumors (GCT) receiving first-line chemotherapy (CT): A meta-analysis of randomized studies.
Authors: Oualla Karima , Miceli Rosalba , Sonpavde Guru , Nicolai Nicola , Raggi Daniele , Giannatempo Patrizia , Boffi Roberto , Busia Alessandra , Mariani Luigi , Salvioni Roberto , Necchi Andrea 
Published: February 2017

482 Background: Little is known about the impact of BLM administration on the development of pulmonary toxicity (PT) in patients (pts) with advanced GCT. This information is critical to further enhance the successful delivery of effective and safe CT in these pts. Methods: Literature was searched for randomized trials of 1st-line CT ( ≥ 3 cycles) for GCT. Descriptive statistics were used to summarize data, dichotomized by BLM-containing vs non containing CT. Univariable and multivariable analyses by random effect models evaluated the predictive role of BLM administration on the development of all grade and G3-4 PT, adjusted for the length of follow-up (FUP, continuous), time-frame of treatment ( ≤ 1997 versus > 1997) % of pts with lung metastases (LM), % of primary mediastinal GCT (PMGCT), IGCCCG risk group. Results: 53 arms of 26 phase II and III trials totalling 6,498 pts were selected: 40 with BLM (n = 5,093) and 13 without BLM (n = 1,405). Median % of pts with LM was 44% (range 22-84%) and 31% (19-79%) in BLM-containing and non containing arms (Wilcoxon test p = 0.505). Median % of PMGCT was 15% (range 0-48%) and 2% (0-13%), respectively (p = 0.146). Median BLM total dose and No. of administrations were 360mg (range 120-375) and 12 (2-24). Median FUP was 52 and 53 months, respectively. The pooled probability of all grade PT was 11.7% (95% CI: 8.4-16.0%) and 1.7% (95% CI: 0.7-4.2%) in BLM-containing and non containing arms. Univariably, BLM administration was associated with the incidence of both all grade (odds ratio [OR]: 7.57, 95%CI: 2.84-20.18, Wald test p < 0.001) and G3-4 PT (OR: 5.19, 95%CI: 1.57-17.16, p = 0.007). Multivariably, BLM administration was significantly associated with the incidence of all grade PT (OR: 4.14, 95%CI: 1.36-12.59, p = 0.012) and trended to significance for G3-4 toxicity (OR: 2.24, 95%CI: 0.91-5.51, p = 0.080). Conclusions: In this meta-analysis, BLM administration was significantly associated with the development of PT in pts with GCT. The quantification of the magnitude of incidence of PT provided here might be useful to optimize the delivery of non-PEB CT in the 1st-line setting.