bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic profiling of muscle invasive bladder cancer to predict response to bladder-sparing trimodality therapy.
Authors: Miyamoto David Tomoaki , Gibb Ewan , Mouw Kent William , Liu Yang , Wu Chin-Lee , Drumm Michael , Lehrer Jonathan , Ashab Hussam Al-Deen , Erho Nicholas , Du Plessis Marguerite , Ong Kaye , Shipley William U. , Davicioni Elai , Efstathiou Jason A. 
Published: February 2018

513 Background: Trimodality therapy with TURBT followed by chemoradiation is an acceptable alternative to cystectomy for muscle invasive bladder cancer (MIBC). Genomic profiling has demonstrated MIBC can be divided into molecular subtypes with differing responses to chemotherapy. We explored the utility of genomic data to select patients for bladder-sparing trimodality therapy. Methods: Transcriptome wide gene expression profiles were generated for 189 MIBC TURBT samples from patients treated with trimodality therapy at a single institution. Of these, 103 passed microarray QC. Molecular subtype and expression of bladder cancer genes were assessed for association with overall and disease-specific survival. Transcriptome wide differential expression analysis was used to explore gene set enrichment in trimodality therapy response groups. Results: The chemoradiation cohort (n = 103) had a median followup of 6.9 years for alive patients, and was classified into four subtypes: basal (n = 44), basal claudin-low (n = 12), infiltrated luminal (n = 17) and luminal tumors (n = 30). There was no significant difference in overall or disease-specific survival by subtype. However, higher expression of the luminal-associated PPARG was correlated with increased survival after adjusting for subtype and clinical factors (HR = 0.52, p = 0.002). In contrast, a p53 signature predicted worse survival after adjusting for clinical factors (HR = 1.92, p = 0.022). Elevated mRNA expression of the DNA damage repair gene MRE11 was associated with improved survival in the trimodality cohort (HR = 0.69, P = 0.031), consistent with its potential role as a predictive biomarker for radiation response. Gene set enrichment revealed differential regulation of immune pathways in trimodality therapy responders relative to non-responders, including enrichment of interferon gamma signaling (p = 0.01) and CXCL9 (p = 0.031), suggestive of an interplay between tumor immunologic microenvironment and response to chemoradiation. Conclusions: Transcriptional profiling of MIBC revealed gene signatures correlated with response to chemoradiation, suggesting the potential of genomics to guide use of trimodality therapy.
Centralization of radical cystectomy for bladder cancer in a universal healthcare system: Early results from a Canadian academic center.
Authors: Rudzinski Jan Krzysztof , Jacobsen Niels , Ghosh Sunita , North Scott A. , Basappa Naveen S. , Kolinsky Michael Paul , Estey Eric , Fairey Adrian S 
Published: February 2018

516 Background: Radical cystectomy for bladder cancer is a complex surgical oncology procedure. Centralization of this procedure to high volume, fellowship-trained surgeons may improve clinical outcomes. Our objective was to compare outcomes of radical cystectomy before and after centralization of care. Methods: A retrospective analysis of data from the University of Alberta Radical Cystectomy Database was performed. Eligible subjects were those with histologically proven urothelial carcinoma of the bladder (cTanyN1-3M0) undergoing curative intent surgery. Patients were classified into pre-centralization era (1994-2007; N = 523) and post-centralization era (2013-present; N = 134) cohorts for analyses. Pre-centralization era patients were treated by 1 of 11 urologic surgeons at 2 academic teaching hospitals. Post-centralization era patients were treated by 1 of 2 fellowship-trained urologic oncologists at 1 academic teaching hospital. Outcomes were overall survival, 90-day mortality rate, positive surgical margin (R1) resection rate, total number of lymph nodes evaluated, and 90-day blood product transfusion rate. The Kaplan-Meier method and multivariable regression analyses were used to analyze survival outcomes. Statistical tests were two-sided (p≤0.05). Results: The median follow-up duration in the pre- and post-centralization era was 33 months and 16 months, respectively. The predicted 2-year overall survival rate was 62% in the pre-centralization era and 84% in the post-centralization era (Log rank P = 0.0007; multivariable HR 0.40, 95% CI 0.24 to 0.68, P < 0.0001). Treatment in the post-centralization era was associated with lower 90-day mortality (6.3% versus 1.5%, multivariable OR 0.23, 95% CI 0.06 to 0.99, P = 0.049), R1 resection (13.0% versus 1.5%; multivariable OR 0.07, 95% CI 0.01 to 0.51, P = 0.009), and 90-day blood product transfusion (59% versus 6%, P < 0.0001) as well as higher total number of lymph nodes evaluated (7 versus 30 lymph nodes, P < 0.0001). Conclusions: Surgical treatment in the post-centralization era was associated with superior survival, cancer control, and perioperative outcomes.
Perioperative nutrition status of radical cystectomy patients.
Authors: Metcalf Meredith , Hamilton-Reeves Jill , DeRuyter Martin , Bishop David , Hand Lauren , Holzbeierlein Jeffrey M. , Lee Eugene 
Published: February 2018

517 Background: Radical cystectomy patients are a vulnerable population, with up to 65% suffering complications and 26% readmitted within 90 days. Patients with aggressive bladder cancer are at high risk for malnutrition. Furthermore, malnutrition is a recognized risk factor for poorer outcomes following radical cystectomy. Unclear is the longitudinal assessment of malnutrition during the entire perioperative time frame of the radical cystectomy. Methods: We initiated a prospective, feasibility pilot trial (NCT NCT02942121) evaluating the usage of a healthcare application in the perioperative management of patients undergoing radical cystectomy. As a secondary aim of this prospective trial, we evaluated the perioperative malnutrition status of each participant using the validated Patient-Generated Subjective Global Assessment (PG-SGA). This assessment was administered by registered dieticians at baseline prior to radical cystectomy and at postoperative visits: 2 week, 6 weeks, and 12 weeks. No nutrition interventions occurred during the course of the trial in order to evaluate the natural longitudinal nutritional status of this patient population. Results: Enrollment has been completed with twenty patients. Thus far, 18 patients have completed baseline PG-SGA evaluation: 13 (72%) patients were well nourished, 3 (17%) had moderate malnutrition, and 2 (11%) were severely malnourished. 11 participants have completed their 2 week visit with all but one having decrease in their PG-SGA score. Interestingly, all six patients who have completed the 12 week visit have returned to their baseline rating of the PG-SGA score. Conclusions: Patients undergoing radical cystectomy for bladder cancer are already at risk for malnutrition, which is exacerbated post-operatively. The recovery to baseline is a slow process and may be a window for impactful nutritional interventions designed to lessen the burden of surgery. Clinical trial information: NCT02942121. [Table: see text]
Clinical and molecular characterization of urothelial cancer developing after pelvic radiation.
Authors: Rose Tracy Lynn , Kardos Jordan , Wobker Sara , Milowsky Matthew I. , Kim William Y. 
Published: February 2018

518 Background: The development of urothelial cancer (UC) after pelvic radiotherapy (RT) is an increasingly recognized phenomenon. Numerous studies show a relationship between ionizing radiation and urothelial dysplasia and DNA damage. It is not known if UC that develops after pelvic RT is associated with a distinct molecular signature, which could have treatment implications for this subset of UC. Methods: The University of North Carolina (UNC) Genitourinary Oncology Database was queried for cases of UC between 01/2012 and 06/2016 in patients with prior pelvic RT. Demographics, clinical stage, and details of prior RT were collected. Patients with available archival FFPE tumor tissue underwent next generation targeted exome sequencing per the UNCSeq pipeline. Somatic mutations and copy number alterations were analyzed. Total mutation burden (TMB) (mutations per total Megabase region of 30X coverage, mut/Mb) and insertion-to-deletion (indel) ratio was calculated. Wilcoxon rank sum was used to compare TMB and indel ratio of RT-associated cases with all cases of UC sequenced at UNC. Results: 38 patients with UC developing after prior pelvic RT were identified. 68% had muscle-invasive UC. Median age was 76. Prior RT was for the purpose of prostate cancer treatment in all patients. 26% had received external beam radiotherapy, 29% brachytherapy, and 16% both (29% unknown). Median time from RT to diagnosis of UC was 8 years. Ten patients with muscle-invasive UC had tumors available for sequencing. The most commonly identified somatic alterations were TP53 in 60%, RB1 40%, CREBBP 30%, ELF3 30%, HLA-DRB1 30%, KDM6A 30%, and MLL2 30%, including co-occurrence of TP53 and RB1 mutations in 30% of patients. The median TMB was 12.1 mut/Mb, significantly lower than the median TMB of 25.6 mut/Mb in all cases of UC sequenced at UNC (p = 0.006). The indel ratio was not different between the two groups (p = 0.11). Conclusions: UC that develops after pelvic RT is a frequent entity that occurs years after RT. Tumors of patients who received prior RT had a lower overall TMB than other UC tumors, suggesting that RT-induced UC may be a different entity than carcinogen-induced UC. Further studies should expand our analysis to confirm these findings.
A new 50-gene molecular subtype classifier: An evaluation of subtype stability and association with response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Choi Woonyoung , Plimack Elizabeth R. , Siefker-Radtke Arlene O. , Dinney Colin P.N. , McConkey David James 
Published: February 2018

519 Background: The bladder cancer basal and luminal molecular subtypes have been associated with differential progression patterns and responses to neoadjuvant chemotherapy. However, they are typically identified by whole transcriptome expression profiling, which may be impractical for most academic centers. To make subtype classification more accessible, we developed a 50-gene basal and luminal subtype classifier and examined its performance in matched tumor specimens, including pretreatment biopsies from patients treated with neoadjuvant chemotherapy. Methods: We refined a 50-gene subtype classifier derived from a oneNN classifier containing >~2000 genes that we previously developed using unsupervised methods. We compared its accuracy against calls made using the original oneNN classifier, including 148 tumors from a neoadjuvant chemotherapy meta dataset. To test subtype stability, tumors in 2 different datasets (30 sets of matched primary and lymph node tumors and 43 sets of matched pre- and post-chemotherapy tumors) were assigned using 50-gene subtype classifier with Linear Discriminator Analysis (LDA) prediction algorithms. Results: In the NAC cohort, patients with tumors assigned to the basal subtype by the 50-gene classifier had better survival outcomes compared to the luminal tumors, consistent with the conclusion generated with the parent classifier (p<0.05). Basal subtype assignments were stable in 62.5 % of pairs, whereas luminal tumors displayed 100% stability. In matched pre- and post-chemotherapy tumors, basal tumors displayed 78% stability while luminal tumors showed 94% stability. Conclusions: Based on these preliminary data, it appears that basal tumors display higher plasticity than luminal tumors with these specific contexts. This plasticity may interfere with precise subtype predictions with tumors assigned to the basal subtype at biopsy.
Using grade of tumor recurrence after BCG to guide further therapy.
Authors: Li Roger , Metcalfe Michael J. , Tabayoyong William , Guo Charles , Nogueras-Gonzalez Graciela M. , Navai Neema , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M. 
Published: February 2018

523 Background: Tumors that recur after BCG therapy are considered to be high risk and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. We aimed to characterize the pattern of bladder cancer progression and cancer specific survival (CSS) in patients with recurrences dichotomized by low grade versus high grade after intravesical BCG treatment. Furthermore, to assess the safety of continued bladder sparing therapy in these patients. Methods: We performed an IRB approved review of our bladder cancer database. Overall, 146 NMIBC patients were found to have tumor recurrence after induction BCG with/without maintenance therapy, 38 with LG and 108 with HG tumors. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity and concurrent CIS were collected and compared between the two groups. The primary endpoint was PFS, with progression defined as the development of MIBC/distant metastasis. In addition, RFS, HG RFS, CFS, and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two-sided and p < 0.05 was considered statistically significant. Results: As dichotomized by grade of recurrent tumor, estimated 5-year PFS was 85.6% (95% CI 60.8 - 95.2%) for those with LG recurrence and 67.9% (95% CI 54.1 – 78.4%) for those with HG recurrence. On KM analysis, patients whose initial LG recurrence on BCG therapy had improved subsequent RFS (5.2 vs. 2.8 yrs, p = 0.007), HG RFS (9.4 vs. 3.0 yrs, p < 0.001), CFS (p < 0.001), and compared to those who had a HG initial recurrence; CSS benefit approached significance (3.7 vs. 2 yrs, p = 0.12). Grade of tumor recurrence after BCG was an independent predictor of PFS (HR 3.7, 95% CI 1.3-10.9, p = 0.016). Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/MUC. However, patients who have low grade recurrences on BCG still may progress and hence should be carefully counselled on bladder sparing therapy.
The role of metastatic burden in cytoreductive/consolidative radical cystectomy.
Authors: Li Roger , Kukreja Janet Baack , Petros Firas G. , Campbell Matthew T. , Nguyen Justin , Nogueras-Gonzalez Graciela M. , Kamat Ashish M. , Pisters Louis L. , Dinney Colin P.N. , Navai Neema 
Published: February 2018

524 Background: The strategy of surgical extirpation of the primary tumor in the setting of metastatic disease has gained acceptance for a variety of solid tumors. The role of cytoreductive/consolidative radical cystectomy (CCRC) for metastatic urothelial cancer (UC) is unknown. We aimed to describe our institutional experience with CCRC for metastatic UC and to investigate clinicopathologic features predicting prolonged cancer specific survival (CSS) following CCRC. Methods: We performed IRB approved review of our bladder cancer database, and identified 32 patients with metastatic cancer originating from the lower urinary tract who underwent CCRC. Of these, two patients had non−UC histology. Baseline demographics, regimen of chemotherapy, clinicopathologic features, and perioperative complications were collected. Progression free survival (PFS) and cancer specific survival (CSS) were estimated from the time of CCRC. Univariate and multivariate Cox regression models were used to identify predictors of improved CSS after CCRC. Results: Of the 32 patients, 19 (59%) had clinical evidence of distant metastases, while 13 were found to harbor occult metastases on the surgical specimen. The most common site of metastasis was the retroperitoneal lymph nodes, found in 17 patients. Solitary metastases were found in 19 patients (59%). Twenty−eight (88%) patients received chemotherapy prior to CCRC. Disease progression was detected in 29 patients after CCRC (median PFS 4.5 mo), while 28 died of metastatic cancer (median CSS 11.7 mo). On multivariate analysis, patients with solitary metastases were found to have improved CSS compared to those with multiple metastases (HR 2.51, 95% CI 1.06−5.92, p = 0.04), with median CSS of 16.9 mo vs. 5.6 mo (p = 0.003). Median postoperative LOS was 10 days. Overall, 59% suffered postoperative complications, including one perioperative mortality. Conclusions: CCRC is feasible in the setting of metastatic UC, with comparable perioperative morbidity and mortality to RC with curative intent. Patients with solitary metastasis demonstrated longer CSS than those with multiple metastases, and should be considered candidates for future trials evaluating the role of CCRC for metastatic UC.
Distress prevalence and associated risk factors within the urothelial cancer population.
Authors: Ralston Laurel , Grivas Petros 
Published: February 2018

526 Background: Prevalence of distress has been estimated as high as 40% in some cancer populations, but minimal literature exists regarding distress in bladder cancer patients. Distress has been linked with multiple negative clinical outcomes, with the Commission on Cancer now requiring standardized distress screening for cancer program accreditation. The purpose of this study is to identify prevalence of distress, associated clinical risk factors and psychosocial referral trends in the urothelial cancer population. Methods: This was a retrospective review of distress screening outcomes in bladder cancer patients seen in oncology outpatient clinic at an academic medical center between January 1, 2016-October 1, 2017. Established oncology patients are screened for distress every 30 days using the Patient Health Questionnaire-9 (PHQ-9) and/or the NCCN Distress Thermometer (DT). Questionnaires are completed on an electronic tablet at the time of check-in and linked to the Epic electronic medical record in real time. A data capture program was used to query screening outcomes and identify those who met the threshold scores (PHQ-9 > 8, DT > 4). Results: Of 153 patients with a primary diagnosis of bladder, 81 (53%) completed the PHQ-9 (n = 67) or NCCN distress thermometer (n = 16). The overall incidence of distress was 13.6% with an average score of 12.3 on PHQ-9 (n = 10) and 9 on DT (n = 1). Of the patients with elevated distress, there were 7 males and 4 females with an average age of 64 and 77, respectively. All were either married or widowed. Metastasis was documented in 45%. Five were on an antidepressant and only one had mood disorder previously documented in the history. Social work referral occurred for 73% of the patients. One patient had elevated distress in the 6 months subsequent to diagnosis. Of the seven now deceased patients, all had elevated distress within 6 months of death. Conclusions: At 13.6%, the prevalence of distress in urothelial cancer patients was less than that in general oncology. Metastatic disease and female gender were risk factors while documentation of a psychiatric condition was not. One unexpected finding was that all now deceased patients had endorsed elevated distress within 6 months of death.
Serum miRNA to predict post-chemotherapy viable disease in testicular non-seminomatous germ cell tumor patients.
Authors: Leao Ricardo Romao Nazario , Van Agthoven Ton , Figueiredo Arnaldo , Fadaak Kamel , Castelo-Branco Pedro , Jewett Michael A.S. , Sweet Joan , Ahmad Ardalan , Anson-Cartwright Lynn , Bedard Philippe L. , Chung Peter W. M. , Hansen Aaron Richard , Warde Padraig Richard , O'Malley Martin , Looijenga Leendert , Hamilton Robert James 
Published: February 2018

546 Background: Retroperitoneal lymph node dissection (RPLND) is recommended for residual masses > 1cm post-chemotherapy (pc) for nonseminomatous germ cell tumors (NSGCT). There is no reliable predictor for pcRPLND histology and up to 50% will harbour necrosis/fibrosis only, thus rendering a potentially morbid surgery to be of limited therapeutic value. Objective: To evaluate the ability of defined serum microRNA (miRNA) using the ampTSmiR test to predict residual viable NSGCT after chemotherapy. Methods: Serum miRNA levels (miR-371a-3p, miR-373-3p and miR-367-3p) were measured in 82 patients (cohort A = 39, cohort B = 43) treated with orchiectomy, chemotherapy and pcRPLND to predict viable GCT post-chemotherapy. Outcomes, measurements and statistical analysis: miRNA levels were compared to clinical characteristics, serum tumor markers and correlated with presence of viable GCT (vs. teratoma; vs. necrosis/fibrosis). miRNA-discriminative capacity was determined by receiver operating characteristic (ROC) analysis. Results: Serum miRNA were associated with stage at the time of chemotherapy and declined significantly post-chemotherapy. Patients with fibrosis/necrosis and teratoma had a significant decline in all three miRNA levels after chemotherapy, while those with viable disease had very little change. Patients with necrosis/fibrosis demonstrated similar miRNA levels as patients with residual teratoma. miR-371a-3p demonstrated the highest discriminative capacity [area under the curve (AUC) 0.874, CI 95% 0.774 - 0.974 p < 0.0001] for viable disease post chemotherapy. If considering a more relaxed cut-point of 3cm before consideration of pcRPLND, miR-371a-3p correctly stratified all patients with residual retroperitoneal lesions ≤ 3 cm ( p= 0.02; 100% sensitivity). Conclusions: Our study is the first to explore a miRNA-based serum test to determine histology in post-chemotherapy residual masses and we demonstrated the value of miR-371a-3p to predict presence of viable GCT. Prospective studies are required to confirm its clinical utility.