bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating cell cycle progression score as a prognostic marker for non-muscle invasive bladder cancer (NMIBC).
Authors: Weight Christopher J. , Murugan Paari J , Chesla David , Tejpaul Resha , Soubra Ayman , Boshoven William , Sangale Zaina , Rajamani Saradha , Stone Steven , Lane Brian R. 
Published: February 2018

476 Background: Accurate grading and staging from transurethral resection of bladder tumors (TURBT) is vital for appropriate clinical management. Non-muscle-invasive bladder cancer (NMIBC) can recur progress with higher grade and or stage progression to MIBC, requiring radical intervention with poorer prognosis. Further, grade and stage may change in 20-50% of TURBTs following re-review by expert GU pathologists Objective measures of stage and grade might offer additional and/or improved risk stratification; therefore we evaluated a molecular RNA signature as a prognostic marker for NMIBC. Methods: Patients were diagnosed with NMIBC at the University of Minnesota (UM)or Spectrum Health System(SHS) from 2005-2012. A Cell Cycle Progression (CCP) score was determined from the average expression of 36 CCP genes for patients with available FFPE diagnostic TURBT. The combined cohort consisted of 293 patients (UM n = 152, SHS n = 141). Study outcome was time from NMIBC diagnosis to progression to MIBC. Median follow-up for patients who did not experience an event was 4.4 years for UM and 6.9 for SHS. Association with outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. All analyses were stratified by cohort. Results: CCP score was associated with progression to MIBC in univariable analysis [hazard ratio 1.42 (95% CI 1.19, 1.68), p = 4.3x10-5]. Tumor grade and stage were also highly prognostic. CCP score was strongly associated with stage (T1 vs Ta, p < 10-6) and grade (high vs low, p < 10-14) in both cohorts. As a result, CCP score did not provide independent prognostic information in multivariable analysis after adjusting for stage and grade (p = 0.32). There was a significant interaction between stage and CCP score (p = 0.0017), justifying an exploratory analysis of CCP score in Ta disease. In this subset, CCP score trended toward (p = 0.056) after adjusting for grade. Conclusions: In NMIBC, CCP score was highly correlated with tumor stage and grade and could serve as a quantitative measure of clinical parameters. The score may also provide prognostic information regarding risk of progression to MIBC, particularly in patients with Ta disease, but requires additional validation.
Association of upregulation of serine and one carbon metabolism genes with shorter recurrence-free and overall survival in urothelial bladder cancer (UBC).
Authors: Lattanzi Michael , Pacold Michael , Balar Arjun Vasant 
Published: February 2018

477 Background: Antimetabolites (e.g. methotrexate and gemcitabine) are not frequently used in the treatment of most solid tumors, but are effective in the treatment of UBC. Rapid cancer cell proliferation relies on an abundance of serine-derived one carbon units to support macromolecule synthesis. Specifically, PHGDH, which encodes a key enzyme of de novo serine synthesis, is amplified in breast cancer and in melanoma, and small molecule inhibitors of enzymes in this pathway are in early clinical development. However, the enzymes of serine and one carbon metabolism have not been widely investigated in UBC. Methods: We conducted an observational analysis of The Cancer Genome Atlas UBC cohort, focusing on gene expression data from a targeted panel indicated by Yang, et al. to be involved in serine and one carbon metabolism. Univariate Cox proportional hazard models were utilized to identify genes impacting OS and RFS, and a subsequent multivariate model was employed to control for inter-gene associations. Results: Expression data from 14 genes were analyzed among 436 UBC patients, of whom complete data were available for 422. At a median follow-up of 17 months, 188 of 422 patients had died. On univariate analysis, 7 of 14 genes were significantly associated with OS: PHGDH, PSPH, MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 (all P < 0.05). Interestingly, overexpression was associated with worse OS for all but one gene, MTHFD2L (HR 0.74), which is known to be underexpressed by cancer cells in favor of MTHFD2 (HR 1.21). In multivariate analysis, overexpression of PHGDH (HR 1.19, P = 0.008), MTHFD1 (HR 1.33, P = 0.041), and ALDH1L2 (HR 1.21, P < 0.001) were independent predictors of poor survival. RFS analysis was limited by missing data; nevertheless, univariate analyses found MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 to be associated with RFS (all P < 0.05). Conclusions: Within the limits of this observational study, these data suggest that serine and one carbon metabolism is important in the progression and prognosis of muscle-invasive bladder cancer. Subsequent in vitro analyses are needed to validate the prognostic and therapeutic significance of these findings.
Characterization of human bladder cancer patient-derived xenograft in vivo and in organoids.
Authors: Lam Hung-Ming , Liu Yuzhen , Vakar-Lopez Funda , Brown Lisha , Montgomery Robert B. , Corey Eva , Hsieh Andrew Caleb , Wright Jonathan L. 
Published: February 2018

479 Background: To establish and molecularly characterize a human bladder cancer patient-derived xenograft (PDX) in vivo and in an organoid system derived from the PDX for preclinical studies. Methods: Two-mm3 bits of urothelial carcinoma originated from muscle invasive disease excised in cystectomy were implanted subcutaneously into male severe combined immunodeficient mice to establish PDXs. Established PDXs (CoCaB 1) were passaged subcutaneously in SCID mice and histopathology of each passage was compared with the originating tumor. Tumor size was measured weekly by caliper to determine the growth rate of PDXs from early (P1/P2) through late passage (P8/P9). Representative early and late passages were collected for organoid establishment. For both early and late passages, proliferation was assessed by Ki67 in PDXs and organoids, and cell cycle analysis and MTS assay specifically in organoids. RNA sequencing was performed to compare the fidelity of PDX and organoids vs. primary tumor. Results: Histologically, 16 of the 16 (100%) PDXs generated from early through late passage (1-2 tumors per passage) were similar to the original high-grade urothelial carcinoma. In vivo, the latency of PDX establishment decreased upon passage (9 weeks to take in early P1/2 vs. 2 weeks to take in late P8/9) and the growth rate increased upon passage. Concordantly, Ki67 proliferation index increased from 40% in P1 to 95% in P8 and was positively correlated with increasing passage (Spearman R=0.804, p=0.001). Similarly, in organoids, late passage demonstrated a shorter growth doubling time, higher Ki67 proliferation index, and faster progression through cell cycle. Transcriptional analysis showed that the PDX contained 81-92% human transcripts, whereas organoids contained >99% human transcripts. Conclusions: Bladder cancer PDXs histologically represented the originating disease. PDX and organoid systems demonstrated concordant increase in proliferation upon serial passages, suggesting clonal selection may take place in this aggressive tumor type. Despite more mouse stromal content in PDX, PDX and organoid represent two independent model systems with highly similar biological responses that allow therapeutic studies.
Practice patterns and outcomes among patients with N0M0 prostate cancer and a very high prostate-specific antigen.
Authors: Muralidhar Vinayak , Yang David Dewei , Mahal Brandon Arvin Virgil , Rose Brent Shane , Beard Clair , Efstathiou Jason A. , King Martin T. , Martin Neil E. , Orio Peter F. , Nguyen Paul L. 
Published: February 2018

48 Background: There are limited data regarding practice patterns and outcomes among patients with a very high prostate-specific antigen (PSA) level ( > = 98.0 ng/mL) but clinically localized (N0M0) prostate cancer. Methods: We used the National Cancer Database (NCDB) to identify 748,825 patients with prostate cancer diagnosed 2004-2012. We subdivided these patients by PSA level (0-9.9, 10-19.9, 20-39.9, 40-59.9, 60-79.9, 80-97.9, and > = 98.0 ng/mL), nodal status (N0 vs N1) and the presence of distant metastases (M0 vs M1). We determined the rate of definitive LR therapy (pelvic and/or prostate radiation and/or radical prostatectomy) in each group. Overall survival was compared using Cox multivariable regression modeling after adjusting for patient race, income quartile, education quartile, age, and year of diagnosis. Results: Rates of definitive LR therapy for patients with PSA > = 98.0 ng/mL and N0M0 disease were significantly lower than they were for those with N1M0 disease (52.6% vs 60.4%, p < 0.001) or with PSA < 98.0 ng/mL and N0M0 disease (52.6% vs 86.6%, p < 0.001). Among patients with N0M0 disease, 5-year OS decreased with increasing PSA: for PSA levels of 0-9.9, 10-19.9, 20-39.9, 40-59.9, 60-79.9, 80-97.9, and > = 98.0 ng/mL, 5-year OS was 91.6%, 84.3%, 80.2%, 84.1%, 81.8%, 80.2%, and 59.1%, respectively. Among those with N1M0 disease, 5-year OS was 63.2%, which in multivariable Cox regression modeling was not significantly different compared to those with PSA > = 98.0 ng/mL N0M0 disease (adjusted hazard ratio [AHR] 0.99, 95% confidence interval 0.91-1.09, p = 0.942). The survival benefit associated with LR treatment was larger among those with N0M0 high-PSA disease than among those with N1M0 disease (AHR of 0.26 vs 0.41, p-interaction < 0.001). Conclusions: Patients with clinically N0M0 disease but very high PSA ( > = 98.0 ng/mL) have similar outcomes as patients with N1 disease but receive definitive LR therapy at a lower rate. It is possible that patients with N0M0 disease and PSA > = 98.0 ng/mL represent a population that should be treated as more similar to the N1M0 population, rather than the M1 population, including consideration of LR therapy in appropriate contexts.
Effectiveness of transurethral resection (TUR) plus systemic chemotherapy as definitive treatment for muscle-invasive bladder cancer (MIBC).
Authors: Audenet François , Waingankar Nikhil , Ferket Bart , Niglio Scot Anthony , Marqueen Kathryn E. , Mehrazin Reza , Sfakianos John , Galsky Matt D. 
Published: February 2018

481 Background: TUR + neoadjuvant cisplatin-based chemotherapy achieves a pathologic complete response in 30-40% of patients with MIBC. Prior studies have demonstrated that long-term survival is possible for a subset of patients with MIBC treated with TUR plus chemotherapy alone, but such analyses have been limited by small sample sizes and poor generalizability. The objective of our study was to describe the characteristics and outcomes of patients managed with this approach using a large national registry. Methods: Within the National Cancer Database (2004-2012), we identified 1,003 patients who were treated with TUR + multi-agent systemic chemotherapy, without radiation, as definitive treatment for cT2-T4aN0M0 urothelial carcinoma of the bladder. Baseline characteristics were compared relative to those of 12,138 patients treated during the same period of time with radical cystectomy ± perioperative chemotherapy. Treatment outcomes were assessed using Kaplan-Meier analysis. Results: Compared to patients who were treated with cystectomy ± perioperative chemotherapy, patients treated with TUR + chemotherapy alone were significantly older (≥75 years old 37% vs. 30%; p < 0.0001), had a higher clinical T stage (cT3: 14% vs. 12%; cT4: 12% vs 7%; p < 0.0001) and were more frequently treated in non-academic facilities (66% vs. 49%; p < 0.0001). There were no significant differences between groups regarding gender, Charlson comorbidity index, insurance type or income/education level. The 30-day and 90-day mortality with TUR + chemotherapy was 0.2% and 4%, respectively. The 5-year survival rate for all patients treated with TUR + chemotherapy was 30.5% (95% CI 26.8, 34.2), and limited to patients with cT2 disease was 33.1% (95% CI 28.7, 37.5). Conclusions: This large real-world cohort representing the continuum of practice settings in the United States confirms that long-term survival is achievable in a subset of patients treated with TUR + chemotherapy alone for MIBC. Refinement of this bladder-sparing approach integrating putative predictive biomarkers of pathologic complete response is now the focus of recently initiated prospective clinical trials.
Clinicopathological features of lipid cell variant of urothelial carcinoma.
Authors: Hayashi Tatsuro , Kimura Go , Takahashi Keigo , Shibayama Keita , Obayashi Kotaro , Sano Masayuki , Tanabe Kuniaki , Akatsuka Jun , Toyama Yuka , Hamasaki Tsutomu , Kondo Yukihiro 
Published: February 2018

487 Background: Lipid cell variant (LCV) of urothelial carcinoma (UC) which was first described by Mostofi et al in 1999 is a very rare variant of UC. Because it has only been documented in occasional case reports and a small series about this variant since then, clinicopathological characteristics of LCV are not yet clarified. In this study, we assessed the clinicopathological characteristics of LCV experienced in our hospital. Methods: The medical records of patients with LCV, who were treated in our hospital between September 2015 and September 2017, were retrospectively reviewed and analyzed. Results: In this period, of 301 patients undergoing TURBT and 42 patients undergoing nephroureterectomy, 13 patients including 10 patients with bladder cancer and 3 with pelvic ureter cancer, were found to be diagnosed as LCV of UC at our hospital. The median observation period of these patients was 6 months (IQR, 4-9 months). Among 10 bladder cancer patients who had confirmed this variant in transurethral resection of bladder tumor (TURBT) specimens, all cases had concurrent high-grade UC and the most cases had tumor features including pT2 or more local stages and lympho-vascular invasion (LVI) positive. Co-existence of micropapillary and/or plasmacytoid variant were seen in 5 patients. Lymph node metastases were observed in 3 patients, and this variant was histologically confirmed within the lymph node metastatic tissue in one case. No patient had distant metastasis. Among 3 pelvic ureter cancer patients who had undergone nephroureterectomy, all cases had concurrent high-grade UC and the most cases had tumor features including pT3 local stage and LVI positive. Micropapillary variant was coexisted in one patient. No patient had distant metastasis. 7 patients were no evidence of disease and 6 were alive with disease. The estimated median time from surgery to recurrence was not reached. The 6-months disease-free survival rate was 59%. Conclusions: LCV is seen in the patients who have high-grade UC, and tends to be accompanied with other aggressive variants including micropapillary and plasmacytoid. All patients with this variant had advanced stage cancer at presentation with high recurrence rates.
Clinical outcomes of patients with histologic variants of urothelial carcinoma treated with tetra-modality bladder-sparing protocol incorporating consolidative partial cystectomy.
Authors: Kijima Toshiki , Yoshida Soichiro , Yokoyama Minato , Ishioka Junichiro , Matsuoka Yoh , Saito Kazutaka , Kihara Kazunori , Fujii Yasuhisa 
Published: February 2018

490 Background: Trimodality bladder-sparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As some of the histologic variants of urothelial carcinoma (VUC) are more resistant to chemotherapy and radiotherapy compared with pure urothelial carcinoma (PUC), it is still controversial whether bladder-sparing therapy provides comparable disease control in VUC. We have developed a tetra-modality bladder-sparing therapy consisting of maximal transurethral resection (TUR), chemoradiotherapy (CRT), and consolidative partial cystectomy, which has theoretical advantage in locoregional control by surgically eliminating chemo- and radio-resistant cells (Koga et al, Urol Oncol 2013, BJU Int 2012). Methods: After maximal TUR and CRT (40Gy + cisplatin), treatment response was evaluated by cytology, imaging and tumor-site rebiopsy. Complete responders were candidate for consolidative partial cystectomy, while radical cystectomy was recommended for others. VUC identified in maximal TUR samples were categorized according to the 2004 World Health Organization Classification. Response rate to CRT, MIBC recurrence-free survival and cancer-specific survival (CSS) were compared between patients with PUC and VUC. Results: Between 1997 and 2016, 153 consecutive patients with cT2-3N0M0 bladder cancer (median age 69, female/male = 33/120, cT2/3 = 99/54) entered tetra-modality bladder-sparing protocol. VUC was identified in 37 (24%) of the patients, including glandular in 12 (8%), squamous in 11 (7%), micropapillary in 8 (5%), sarcomatoid in 2 (1%), microcystic in 2 (1%), and lymphoepithelioma-like in 1 (0.7%). There was no difference in the response rate to CRT between PUC and VUC (71% vs 84%, p = 0.13). Among the patients with PUC (n = 75) and VUC (n = 31) who underwent partial cystectomy, 5-yr MIBC recurrence-free rates were 92% and 100% (p = 0.21), and 5-yr CSS rates were 93% and 94% (p = 0.64), respectively. Conclusions: Tetra-modality bladder-sparing therapy incorporating partial cystectomy could provide favorable locoregional control and survival for patients with VUC.
Utilization and outcomes of chemoprophylaxis for the prevention of venous thromboembolism following radical cystectomy: A population-based study.
Authors: Reese Stephen , Mossanen Matthew , Zlatev Dimitar V. , Pucheril Daniel , Chung Benjamin I. , Chang Steven Lee 
Published: February 2018

491 Background: Venous thromboembolism (VTE), comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major preventable source of postoperative complications. The risk of VTE in patients undergoing radical cystectomy (RC) for bladder cancer has been estimated at 6%, and the American Society of Clinical Oncology, American Urological Association, and National Comprehensive Cancer Network all recommend perioperative chemoprophylaxis. We performed a population-based analysis to determine the utilization of chemoprophylaxis against VTE in patients undergoing RC. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we retrospectively identified patients who underwent RC for bladder cancer in the US between 2006 and 2015. Administration of chemoprophylaxis within 24 hours of surgery was deemed consistent with recommendations. A subgroup analysis of higher volume hospitals (³10 RC annually) compared outcomes of DVT, PE, and bleeding between patients in hospitals with uniform use versus no use of chemoprophylaxis. Multivariate analysis was used to evaluate predictors of under-utilization of chemoprophylaxis. Results: Among the cohort of 9,133 patients (48,714 patients after weighting adjustment) undergoing RC, 35.1% were administered recommended chemoprophylaxis, with an increase in utilization from 20.7% in 2006 to 49.6% in 2015. Characteristics associated with decreased likelihood of chemoprophylaxis administration included patient age ≥65 years, Charlson Comorbidity Index score ≥2, rural hospital location, commercial insurance, and year of surgery prior to 2010. Patients who received recommended chemoprophylaxis had significantly lower rates of VTE (5.1% vs 6.0%) and PE (2.0% vs 3.1%), but elevated rates of bleeding (12.8% vs 7.7%). Conclusions: The recommended utilization of chemoprophylaxis in a contemporary nationwide cohort of patients undergoing RC is limited despite its notable increase over the course of the study period. Greater compliance with recommended use of chemoprophylaxis following RC may be associated with decreased risk of PE and VTE, but also with increased risk of bleeding.
The impact of treatment at minority-serving hospitals on outcomes for bladder cancer.
Authors: Fletcher Sean A. , Gild Philipp , Cole Alexander P , Vetterlein Malte , Kibel Adam S. , Choueiri Toni K. , Sonpavde Guru , Preston Mark A , Pucheril Daniel , Menon Mani , Sun Maxine , Lipsitz Stuart R. , Trinh Quoc-Dien 
Published: February 2018

492 Background: Healthcare for racial minorities is densely concentrated at a small subset of hospitals in the United States. Understanding long-term outcomes at these minority-serving hospitals is highly relevant to elucidating the sources of racial disparities in cancer care. We investigated the impact of treatment at a minority-serving hospital on overall survival and receipt of definitive treatment for bladder cancer. Methods: Using the National Cancer Database, we identified all patients diagnosed with clinically localized, muscle-invasive bladder cancer between 2004 and 2012. Univariate and multivariable analyses were performed to assess the sociodemographic, clinical, and hospital-level factors influencing overall survival and receipt of definitive treatment (radical cystectomy with or without chemotherapy; trimodal therapy) for bladder cancer. Results: In adjusted analyses, there was no significant difference in overall survival between patients treated at minority-serving hospitals versus those treated at non-minority-serving hospitals (HR: 0.95; 95% CI: 0.90-1.01). There was also no significance in receipt of definitive treatment between the two hospital types (OR: 0.85; 95% CI: 0.68-1.06). Black race was independently associated with increased likelihood of mortality (HR: 1.08; 95% CI: 1.03-1.14) and decreased odds of receiving appropriate definitive treatment (OR: 0.73; 95% CI: 0.66-0.82). Conclusions: There was no difference between minority-serving and non-minority-serving hospitals in overall survival or receipt of definitive treatment. Black patients suffered worse survival and were less likely to receive definitive treatment for bladder cancer regardless of the type of hospital in which they were treated.