bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a genomic classifier for prediction of metastasis following postoperative salvage radiation therapy.
Authors: Den Robert Benjamin , Choeurng Voleak , Howard Lauren , de Hoedt Amanda , Du Plessis Marguerite , Yousefi Kasra , Lam Lucia L.C. , Buerki Christine , Trabulsi Edouard John , Dicker Adam , Davicioni Elai , Karnes Jeffrey , Freedland Stephen J. 
Published: February 2017

4 Background: Management of patients with a postoperative rising prostate-specific antigen (PSA) level is complex. Additional local treatment such as salvage radiation therapy (SRT) may be sufficient for many patients but some may require concurrent systemic therapy in order to delay or prevent metastatic disease. As PSA recurrence on its own is a poor surrogate for metastatic disease we hypothesized that the Decipher genomic classifier (GC), a validated predictor of metastasis may be able to better distinguish those patients where additional therapy is beneficial from those where SRT on its own is likely sufficient. Methods: Genomic classifier (GC) scores were calculated from 170 prostate cancer patients, who received SRT at the Veteran Affairs Medical Center Durham, Thomas Jefferson University and Mayo Clinic, between 1990 and 2010. SRT was defined as administration of RT with Pre-RT PSA levels > 0.2 ng/ml. GC and CAPRA-S scores were compared using survival c-index, competing-risks and Cox regression analysis for the prediction of metastasis. Results: Survival c-index for predicting metastasis 5 years post SRT was 0.85 (95% CI: 0.73-0.88) for GC and 0.63 (95% CI: 0.49-0.77) for CAPRA-S. The cumulative incidence of metastasis at 5 years post-SRT was 2.7%, 8.4%, and 33.1% for low, average, and high GC scores (p < 0.001) and 16.9%, 2.3% and 17.2% for low, average and high CAPRA-S scores (p = 0.113). In univariable analysis only GC, extraprostatic extension, path GS and Pre-RT PSA were significant predictors of metastasis. In multivariable analyses with clinical risk factors or the CAPRA-S risk model, GC was the only independent predictor of metastasis with a HR of 1.63 (1.22-2.18, p < 0.001) for a 10% unit increase in risk score. Conclusions: In patients treated with postoperative SRT for PSA recurrence, GC is a powerful predictor of metastasis. Patients with low Decipher have excellent prognosis with SRT and may avoid concurrent hormonal therapy. Patients with high Decipher risk are at highest risk for metastatic disease and SRT failure and may benefit from intensified systemic therapy.
A dual stable isotope method by LC-MS/MS to define patterns of androgen metabolism in localized versus advanced prostate cancer.
Authors: Dai Charles , Chung Yoon-Mi , Klein Eric A. , Sharifi Nima 
Published: February 2017

40 Background: Prior work has shown that androstenedione (AD) rather than testosterone (T) is the preferred substrate of 5α-reductase for dihydrotestosterone (DHT) synthesis in castration-resistant prostate cancer. However, patterns of metabolism in hormone-naive prostate cancer are still poorly defined. Previously, we reported on the utility of dual radioisotope labeling of steroid precursors to characterize androgen metabolism in localized prostate tissue. We now describe an alternative approach via stable isotope labeling and analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which has unique advantages over the former method. Methods: LNCaP cell lines and prostate tissue from patients undergoing radical prostatectomy for localized cancer were incubated in serum-free media, spiked with 13C-labeled AD and 2H-labeled T. Media was collected at 7, 24, and 48 hours of incubation. Steroids were extracted, separated, and then analyzed by way of LC-MS/MS to identify labeled metabolites of AD and T. Results: Incubation of labeled AD and T resulted in conversion over time to both 13C-labeled and 2H-labeled downstream metabolites, 5α-dione and DHT. Although both precursors contributed to 5α-dione and DHT formation, the steroid of origin could be determined on the basis of differential labeling. In ex-vivo tissue incubations, unlabeled 5α-dione was also observed, which was distinguishable from its stable isotopic form and most likely represents endogenous steroid. Conclusions: Both cell lines and tissue appear to metabolize labeled AD and T, and formation of DHT occurs through both precursors. Furthermore, the presence of endogenous 5α-dione suggests that alternative pathways of DHT synthesis, which bypass T, may be naturally accessible in the hormone-naïve setting. We propose a robust ex-vivo technique to readily track simultaneous pathways of DHT synthesis in prostate cancer. Future work will focus on defining metabolic phenotypes of localized prostate cancer and specific patterns of flux under different hormonal and pharmacologic conditions.
Evaluation of early response to neoadjuvant chemotherapy in muscle-invasive bladder cancer using dynamic contrast-enhanced MRI and diffusion weighted MRI: MARBLE study.
Authors: Pearson Rachel Anne , Thelwall Pete E , Snell Jim , McKenna Jill , Pieniazek Piotr , Fitzgerald Emily Louise , Heer Rakesh , McMenemin Rhona Margaret , Pedley Ian D. , Azzabi Ashraf S. , Newell Herbie , Maxwell Ross J. , Plummer Elizabeth R. , Frew John A. 
Published: February 2017

403 Background: Functional imaging techniques which evaluate early treatment responses may identify non-responders who would benefit from a switch in therapy. This is a prospective feasibility study of serial diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI scanning in patients undergoing neoadjuvant chemotherapy for muscle-invasive bladder cancer. Methods: Scans were performed before and during chemotherapy (10-17 days after the first and second cycles). A repeatability DW-MRI scan was acquired on the first visit. Regions-of-interest (ROI) encompassing the entire tumour were defined. Analysis of MRI parameters was undertaken and related to findings from the routine restaging CT scan performed after 3 cycles of chemotherapy. Results: 10/16 patients were male, median age 59 years, 14/16 had T3/4 disease, and 5/16 were node positive. 10/16 have completed 3 or 4 cycles of chemotherapy to date and attended for the restaging CT scan. Radiological response was identified in all cases. In the DW-MRI analysis there was no significant difference in mean tumour ADC or tumour volume between baseline and repeatability scans (mean ADC 1.19 and 1.2 respectively, n=16). Visual assessment showed a fall in contrast agent uptake within the primary bladder tumour after treatment. Conclusions: The scanning protocols enabled visualisation of the bladder tumours and derivation of kinetic parameters. DW-MRI measurements were comparable between baseline and repeat scan, suggesting that a change in ADC was more likely to be attributable to treatment response or disease progression than measurement error or inherent variation. Statistically significant rises in mean ADC and decreases in tumour volume were observed early in the treatment pathway. No patients progressed on treatment in this study. Larger studies of DCE and DW-MRI as surrogate response imaging biomarkers in bladder cancer are recommended. Clinical trial information: Study ID 14489. [Table: see text]
Mitomycin-C induction and maintenance topical therapy for upper tract urothelial carcinoma
Authors: Wagenheim Gavin Neal , Papadopolous John , Navai Neema , Davis John W. , Karam Jose A. , Kamat Ashish M. , Wood Christopher G. , Dinney Colin P. N. , Matin Surena F. 
Published: February 2017

411 Background: Reported recurrence rates following endoscopic treatment of upper tract urothelial carcinoma (UTUC) are high, from 30% to 70%. Adjuvant BCG topical therapy results are inferior to what is seen in adjuvant treatment of bladder cancer. This is likely due to difficulty in definitive delivery to the upper tract and the absence of a reservoir for dwell times. There is limited reported use of adjuvant mitomycin-c (MMC) for UTUC, and to our knowledge no reported experience of topical delivery using the SWOG maintenance regimen. We hypothesized that a chemotherapeutic agent may be effective topical therapy of the upper tract, particularly when given using SWOG recommendations. We report efficacy, safety, and tolerability of this approach. Methods: We reviewed charts of patients undergoing primary endoscopic biopsy/resection and ablation of an UTUC, recording clinical, pathologic, laboratory, and follow up information. Patients were offered induction and maintenance topical therapy after endoscopic control. MMC was given as initial adjuvant topical agent for 6 weeks induction and 3 weeks maintenance for up to 2 years per SWOG protocol. Delivery was either via percutaneous nephrostomy or ureteral catheter, per patient preference. Results: 28 patients were identified, 21 (75%) low grade and 7 (25%) high grade. Delivery of MMC was via percutaneous nephrostomy in 29% and ureteral catheter in 71%. 46% were treated on an imperative basis, 46% elective, and 7% palliative. No patients discontinued therapy due to intolerance, and 61% received maintenance. Only 11% of patients undergoing induction and 6% maintenance incurred complications. With a mean follow up of 22 months (range 1−79), recurrence-free, progression-free, and nephroureterectomy-free survival in all patients, low-grade patients, and high-grade patients was 68%, 67%, and 71%; 89%, 90%, and 86%; and 89%, 90%, and 86%, respectively. Conclusions: In patients with complete endoscopic control, upper tract topical instillation of MMC induction and maintenance via percutaneous nephrostomy or ureteral catheter is a well−tolerated, feasible, and perhaps beneficial treatment of low-grade and possibly high-grade tumors.
Are we systemically under treating cisplatin-eligible patients with muscle invasive bladder cancer (MIBC) who are undergoing bladder preservation by chemoradiotherapy?
Authors: Sridhar Srikala S. , Bashir Shaheena , Chung Peter W. M. , Zlotta Alexandre , Fleshner Neil Eric , Bristow Robert G. , Kulkarni Girish S. , Teich Miriam , Alimohamed Nimira S. , Lo Gregory 
Published: February 2017

417 Background: Neoadjuvant chemotherapy (NC) improves survival in MIBC pts regardless of local management-cystectomy or chemoradiation. NC use with chemoradiation has been limited as these pts are often elderly, frail and cisplatin-ineligible. But, as more fit, cisplatin-eligible pts opt for chemoradiation it is critical that we re-evaluate the feasibility and outcomes of giving NC followed by chemoradiation. Methods: We reviewed 25 MIBC pts with cT 2-4 N 0-1 M 0, undergoing chemoradiation between 2008-2014 at the Princess Margaret and Durham Regional Cancer Centers. All pts received NC with gemcitabine-cisplatin (2-4 cycles) then external beam radiation (median dose 60Gy) with concurrent cisplatin. Toxicities were recorded using CTCAE v 3.0. Response and outcomes were assessed by cystoscopy and imaging. Median follow-up was 29.7 mos and 6 pts had < 2 yrs of follow-up. Kaplan Meier analysis was used for survival. Results: Main reasons for a chemoradiation approach were pt preference 15/25 (60%) and comorbidities 10/25(40%). At diagnosis, median age was 69 (49-85), 76% were male, all were ECOG PS 0/1, median CrCl was 58.5 ml/min and 7/25 (28%) had hydronephrosis. CIS was seen in 10/25 (40%), LVI in 3/25 (12%) and node positivity in 2/25 (8%). All but 1 patient completed planned NC, where main Grade 3/4 toxicities as expected were neutropenia and infection. All planned radiotherapy and 83% of planned concurrent chemotherapy was given. Maximal TURBT was done in 76%. Cystoscopically post NC, 12/15 (80%) had a CR, 1/15 (7%) had CIS, and 2/15 (13%) had residual disease. Of the 12 pts with a CR, radiologically 4/12 had a CR, 2/12 had a PR and 6/12 had SD. Four pts required salvage cystectomy for local recurrence, 4 pts developed metastases and have died. Median OS was not reached, but the 2 yr OS rate was 73.8% (95% CI 50.3-87.4%). Conclusions: NC followed by chemoradiation, showed cystoscopic CR rates of 80% post NC and 2 yr OS rates of 73.8% suggesting this approach should be considered in cisplatin-eligible MIBC pts undergoing chemoradiation. Comparing outcomes between matched MIBC pts receiving NC and then chemoradiation or cystectomy also appears warranted.
Venous thromboembolism (VTE) risk in patients with localized urinary tract tumors (UTT).
Authors: Ramos Jorge , Wong Yu-Ning , Crabb Simon J. , Niegisch Guenter , Bellmunt Joaquim , Ladoire Sylvain , Hussain Syed A. , Baniel Jack , Golshayan Ali Reza , Powles Thomas , Rosenberg Jonathan E. , De Giorgi Ugo , Vaishampayan Ulka N. , Agarwal Neeraj , Pal Sumanta K. , Harshman Lauren Christine , Necchi Andrea , Recine Federica , Galsky Matt D. , Yu Evan Y. ,   RISC Investigators
Published: February 2017

422 Background: VTE is common in cancer patients, but there is limited data in patients with UTT. We previously demonstrated that non-urothelial histology, cardiovascular disease (CVD) or CVD risk factors or renal dysfunction increased VTE risk in metastatic UTT. In this study, we assessed the frequency and risk factors for VTE in localized disease. Methods: Data was collected via an electronic data capture platform from 29 centers. Patients diagnosed with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients without a date of diagnosis, last follow up, or VTE data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis, excluding VTEs diagnosed in the metastatic setting. Chi-squared analyses were used to assess differences in VTE rates for various patient, therapy, and tumor-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Results: 1131 patients were eligible for analysis. Perioperative chemotherapy was utilized in 46.9% (530/1131) of patients. 70.8% (801/1131) underwent definitive surgical intervention. There were 64 VTEs (cumulative incidence 5.7%). Treatment with chemotherapy (p = 0.609) or surgery (p = 0.886) did not increase VTE risk. In the univariate analysis, non-urothelial histology (p = 0.025), CVD or CVD risk factors (p = 0.004), renal dysfunction (p = 0.023), and radiation to the primary tumor (p = 0.048) were statistically significant factors. Multivariate analysis demonstrated that non-urothelial histology and CVD or CVD risk factors were associated with increased VTE risk (table). Conclusions: The VTE incidence of 5.7% in localized disease is lower than our previously reported rate in the metastatic setting (8.2%). Consistent with our findings in metastatic UTT, non-urothelial histology and CVD or CVD risk factors increase VTE risk in localized disease. Additional analyses to control for baseline demographics in patients treated with surgery and chemotherapy will be performed. [Table: see text]
Early toxicity in a randomized trial of high dose-rate (HDR) brachytherapy as monotherapy for low- and intermediate-risk prostate cancer.
Authors: Morton Gerard , Chung Hans T. , McGuffin Merrylee , Zhang Liying , Ravi Ananth , D'Alimonte Laura , Loblaw Andrew 
Published: February 2017

44 Background: Evidence supports the use of high dose-rate brachytherapy (HDR) as monotherapy for selected patients with low- and intermediate-risk prostate cancer when given in schedules of 4 or more fractions. There is limited data on the safety and efficacy of HDR given in fewer fractions. Our purpose is to report on acute toxicity (within 3 months) and early changes in health-related quality of life in a randomized trial comparing a single fraction and a 2-fraction protocol. Methods: A single center, randomized phase II clinical trial of HDR either as a single fraction of 19 Gy (1F), or as two fractions of 13.5 Gy (2F) given 1 week apart was undertaken between June 2013 and April 2015. Eligible patients had NCCN low- or intermediate-risk disease, a prostate volume < 60 cc, International Prostate Symptom Score (IPSS) of 18 or lower, no previous prostate surgery and no use of androgen deprivation therapy. Treatment was delivered using an out-patient ultrasound-based technique. Follow-up assessment was with CTCAE v4, IPSS and Expanded Prostate Composite Index (EPIC). Results: A total of 168 patients were randomized: 86 to 1F and 82 to 2F arms. Median age was 65 years, median prostate volume was 35 cc, and 91% had intermediate risk. Median follow-up was 12 months. Only 3 patients (1.8%) experienced acute grade 2 GI toxicity. The percentage of acute grade 2 GU toxicities is as follows: retention (48%), frequency (20%), urgency (4%). One patient experienced grade 3 hematuria. Ten patients (6%) had urinary retention but only 4 (2.5%) required use of a catheter for longer than 2 days. There was no difference in rate of grade 2 toxicity between treatment arms; the only factor associated with grade 2 urinary retention on univariate and multivariate analysis was prostate volume (p=0.0033). Mean EPIC urinary (p=0.0016) and sexual domain scores (p<0.0001) were lower at 6 months with no difference between treatment arms. Bowel and hormonal domain scores were unchanged. Conclusions: HDR 19 Gy x 1 or 13.5 Gy x 2 is very well tolerated acutely with no acute bowel toxicity. Mild to moderate acute urinary symptoms are common. No difference is found in acute toxicity or early health-related quality of life between treatments. Clinical trial information: NCT01890096.
Identification of novel immunomodulatory tumor biology through comprehensive characterization of a metastases-specific epigenome in patients with metachronous primary and metastatic urothelial carcinoma (UC) tumor pairs.
Authors: Hahn Noah M. , Cramer Harvey M , Badve Sunil S. , Cheng Liang , Gokmen-Polar Yesim , Miller David F , Buechlein Aaron , Rusch Douglas B , Fang Fang , Frankhouser David , Bundschu Ralf , Javkhlan-Ochir Ganbat , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Gardner Thomas A. , Yan Pearlly , Nephew Kenneth P , Marchionni Luigi 
Published: February 2017

452 Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The present study aimed to identify uniquely hypermethylated regions in UC metastases compared to their matched primary tumors. Methods: UC patients with paired formalin fixed paraffin embedded tissue samples ( > 75% tumor) from primary and metachronous metastatic tumors were identified. DNA methylation was analyzed on the Illumina HiSeq platform by double-enzyme reduced representation bisulfite sequencing (dRRBS). Results were analyzed by BS-seq within BSmooth open source software. Alignment and methylation estimation was done using Bismark open source software. CpG regions with coverage < 2 in more than 66% of samples were removed to reduce false positive results. Differentially methylated regions (DMRs) in metastases compared to primary tumors were determined by paired t-test. Gene set enrichment analysis (GSEA) of the top 5% DMRs was performed utilizing multiple gene set collections including c7IMMUNO. A false discovery rate of < 10% defined significant DMRs. Results: 15 UC primary/metachronous metastases pairs were analyzed. After filtering for low coverage, 1,781,762 loci remained for analysis. After merging loci within 2500 bp of each other, the top 5% DMRs resulted in 18,452 DMRs. GSEA including the c7IMMUNO gene set identified multiple previously undescribed hypermethylated genes modulating immune function through TGF-beta and Treg signaling including: TGFBR2, TGFBR3, SMAD1, SMAD3, SMAD4, BACH1, BACH2, and VDR all q < 0.05. Conclusions: We identified numerous genes with immunomodulatory functions significantly hypermethylated in UC metastases compared to their matched primary tumors. Our findings provide rationale to examine epigenetic approaches as a means to improve clinical outcomes of UC patients treated with immunotherapy. Our small sample size limits definitive conclusions and warrants validation in independent data sets.
Prognostic value of lymphovascular invasion in squamous cell carcinoma of the urinary bladder.
Authors: Vernez Simone Lucia , Spradling Kyle , Morgan Jacob B , Lotan Yair , Shokeir Ahmed , Abol-Enein Hassan , Mosbah Ahmed , Ghoneim Mohamed , Youseff Ramy F 
Published: February 2017

454 Background: The prognostic value of lymphovascular invasion (LVI) has been well studied in urothelial carcinoma of the bladder (UCB) but not in squamous cell carcinoma (SCC). Herein, we evaluate the association of LVI with oncologic outcomes of SCC following radical cystectomy (RC). Methods: We retrospectively evaluated 1280 patients who underwent RC and pelvic lymph node dissection (LND) for invasive bladder cancer between 1997– 2003 at a single institution in Mansoura, Egypt. Only patients with pure SCC pathology were included. Prognostic significance of LVI was evaluated for patients with SCC. Results: Our cohort included 360 patients with SCC. Median patient age and follow-up were 55 years (20 – 87) and 44 months (0 – 108), respectively. LVI was present in 47 (13.1%) and lymph node metastasis (LN+) was present in 66 (18.3%). In Kaplan-Meier analyses, 5-year disease free survival rates for LVI-/LN- and LVI+/LN- patients were 80.2±3% and 38.9±12% (p < 0.001), respectively; 5-year cancer specific survival rates were 88.2±2% and 50.4±13% (p < 0.001), respectively. Moreover, cancer specific mortality was highest in LVI+/LN- patients (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Multivariate Cox-regression analyses showed that LVI+ status was independently associated with disease recurrence (HR = 2.827; 95% CI: 1.451 – 5.509; p = 0.002 and cancer specific mortality in patients with SCC (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Conclusions: Lymphovascular invasion is a strong independent predictor of oncological outcomes after RC for SCC of the urinary bladder. The incorporation of LVI status into classic prognostic models for SCC of the bladder may lead to improved identification of high-risk patients.