bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective study of a 17-GENE RT-PCR-based assay for prediction of high risk pathology at radical prostatectomy.
Authors: Shore Neal D. , Richardson Tim , Rosenberg Steve , Goldfischer Evan , Lu Ruixiao , Shindel Alan W , Bennett John , Karsh Lawrence Ivan , Korman Howard , Febbo Phillip G. , Denes Bela Stephen 
Published: March 2017

36 Background: A biopsy-based 17 gene tissue-based RTPCR assay (Oncotype Dx Genomic Prostate Score, GPS) has been validated in retrospective cohorts as a predictor of adverse pathology and biochemical recurrence in prostate cancer (PCa) patients who underwent radical prostatectomy (RP). The National Comprehensive Cancer Network (NCCN) recommends that men with pathologic Gleason Score (pGS) > 8, pT3+, and/or Lymph Node positive disease (i.e. high risk surgical pathology, HRSP) consider adjuvant therapy after RP. We report herein on GPS at biopsy as a predictor of HRSP in men presenting with clinically low-risk PCa. Methods: As part of an ongoing observational study of GPS (N = 1200), we performed an exploratory analysis in men who elected RP as initial disease management. Descriptive statistics were reported. Binary logistic regression was performed to determine the association between GPS and HRSP. The odds ratio (OR) per 20 GPS units and 95% confidence interval (CI) were reported. All analyses were conducted with SAS 9.4. Results: Of the 1,200 patients enrolled in the study, 150 (21 sites) selected RP for initial management; 122 (19 sites) had biopsy and surgical pathology data available for analysis.Median age was 63 (range 50-79) years, with 38% > 65 yrs. There were 72 (59%), 39 (32%), and 11 (9%) patients who had NCCN Intermediate-, Low-, and Very Low-Risk disease, respectively Median GPS was 30 (IQR 20-40, range 8-82). Biological risk (GPS+NCCN) differed from NCCN risk in 28 cases (23%). At surgery, 29 /122 (24%) of patients had HRSP; of these, 1 had NCCN Very Low-, 8 had Low-, and 20 had Intermediate-Risk cancer at diagnosis. GPS was a significant predictor of HRSP (OR per 20 GPS units: 2.1; 95% CI: [1.2, 4.0]; p-value 0.02). No other clinical factor was significantly associated with HRSP. GPS remained significant after adjusting for NCCN risk group (OR per 20 GPS units: 2.0; 95% CI 1.1-3.8, p = 0.03). Incorporation of GPS increased the AUC for prediction of HRSP from 0.57 (NCCN alone) to 0.65 (NCCN + GPS) Conclusions: GPS derived from biopsy tissue is an independent predictor of HRSP. This information may be valuable in treatment planning for men with clinically low risk PCa who are at risk for HRSP.
Discerning predictors for gender differences in survival outcomes for patients treated for bladder cancer.
Authors: Kerr Preston , Huo Jinhai , Giordano Sharon Hermes , Kamat Ashish M. , Morales Edwin Edgard , Fang Justin Edwin , Ynalvez Leslie , Dafashy Tamer , Kosarek Christopher David , Ghaffary Cameron , Williams Stephen Bentley 
Published: March 2017

360 Background: Radical cystectomy is an underutilized option for those with refractory non-muscle invasive and muscle-invasive bladder cancer, however, use of radical cystectomy may differ according to gender. We wanted to discern receipt and timing of radical cystectomy as well as survival outcomes according to gender. Methods: A total of 49,974 patients aged 66 years or older diagnosed with clinical stage I-IV bladder cancer from January 1, 2002 to December 31, 2011 using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. We used univariate and multivariable regression analyses to identify factors predicting the use of radical cystectomy. Cox proportional hazards models were used to analyze survival outcomes. Generalized linear models were performed to determine association between gender and delayed radical cystectomy. Results: A total of 49,974 patients were diagnosed with stage I to IV bladder cancer. 36,959 (74%) were male patients. Women were older, non-Caucasian race/ethnicity, with increased comorbidities and presented with more advanced disease (all p<0.001). Women were more likely than men to receive radical cystectomy across all clinical stages (stage I, relative risk [RR] 1.53, 95% confidence interval [CI] 1.27-1.84, p<0.001; stage II, RR 1.52, 95% CI 1.37-1.70, p<0.001; stage III, RR 1.26, 95% CI 1.15-1.39, p<0.001; stage IV, RR 1.31, 95% CI 1.17-1.47, p<0.001). Women had lower cancer-specific survival with stage II (hazard ratio [HR] 1.20, 95% CI 1.09-1.32, p<0.001), stage III (HR 1.44, 95% CI 1.23-1.68, p<0.001), and stage IV (HR 1.29, 95%CI 1.17-1.43, p<0.001) disease. Delay from diagnosis to radical cystectomy was associated with worse survival. Conclusions: Gender differences persist with women significantly more likely to undergo radical cystectomy independent of clinical stage. After controlling for tumor characteristics and neoadjuvant chemotherapy, women have significantly worse cancer-specific survival than men. Delay to surgery did not account for this decreased survival among women. These findings support further research discerning bladder carcinogenesis according to gender.
Molecular characterization of urothelial carcinoma of bladder and upper urinary tract.
Authors: Hwang In Gyu , Heo Mi Hwa , Kim Hee Kyung , Lee Hansang , Cho Jinhyun , Kim Youjin , Lee Sang-Cheol , Kang Jung Hun , Park Se Hoon 
Published: March 2017

361 Background: It is a considerable unmet need to increase understanding of the molecular basis of urothelial carcinoma (UC) to refine the clinical decision-making process. We also aim to assess that whether we can apply similar principles in the management of upper tract UC (UTUC) based on the behavior of urinary bladder UC (UBUC). Methods: To study the molecular nature of UC, we performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes using the Ampliseq v2. Copy number variations (CNVs) were detected with nCounter assay. Genetic alterations between UTUC and UBUC were compared. Results: Tumor samples from 34 UTUC and 63 UBUC patients were eligible for analyses. Two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was, although statistically insignificant, longer in UTUC than UBUC patients (59 vs. 41 months, P = 0.63). In total, we found 920 genetic alterations from 97 samples: most common type of somatic mutation was single nucleotide variants (SNVs; 494/525, 94.1%). After analyzing total genomic alteration frequency, we found that the frequency of CNVs was not significantly different between UTUC and UBUC group: most commonly observed mutation in the UBUC patients was TP53 (18.9%), followed by KDR (7.2%), FGFR3 (4.1%) and PIK3CA (4.1%). In the UTUC patients, TP53 (22.9%), KDR (6.5%), NOTCH1 (5.3%) and FGFR3 (4.1%) are most frequentl somatic mutations. We also identified five translocations in total UC cohort including one case with FGFR3–TACC3 (Chr4) fusion. Conclusions: Within the limitation of small sample size, we found no relevant differences in somatic mutation frequencies between UTUC and UBUC, indicating a basis for similar management strategies.
Outcomes and survival in nonbilharzial pure squamous cell bladder cancer in patients undergoing curative radical cystectomy.
Authors: Kukreja Janet Baack , Ismaeel Nourhan , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul 
Published: March 2017

363 Background: Pure squamous cell cancer of the bladder is uncommon in the United States. Because squamous cell bladder cancer is rare, there are no large studies with details on optimal preoperative neoadjuvant therapies and long-term outcomes. To improve the overall knowledge of the disease this study sought to provide a contemporary update in a single center cohort. Methods: A retrospective cohort study was performed. 57 patients had a radical cystectomy (RC) for pure nonbilharzialsquamous cell bladder cancer between 1995 and 2015. Demographics, risk factors for squamous cell bladder cancer, pathology, and outcomes were reviewed and compared with descriptive statistics. Advanced disease was defined as ≥ T3/T4 disease and any positive lymph node metastasis. Logistic regression was used to identify predictors of overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS). Kaplan-Meier curves were used for survival prediction. Results: With a median follow up of 24 months (IQR 9.7-131.8 months), 12 (21.4%) had a recurrence. The median time to recurrence was 15.5 months (IQR 5.0-20.0 months). Recurrence was most common in the pelvis, n = 5(62.5%). 20 had neoadjuvant chemotherapy (NAC), 16 of which it was combined with external beam radiation (XRT). 50.8% of patients had advanced pathology. 5-year OS was 59.7%. To predict RFS all of the following were adjusted for: age, stage, advanced pathology, nonbilharzialsquamous cell risk factors, lymphovascular invasion, and number of lymph nodes removed at RC. Predictors of RFS were combined NAC and XRT, pathologic T-stage, advanced disease (p = < 0.01, p = 0.02 and p = 0.02, respectively). Predictors of DSS were pathologic T-stage and node positive disease (p = 0.04 and < 0.01, respectively). OS was best predicted by clinical stage, p < 0.001. Conclusions: The combination of NAC and preoperative XRT may provide a RFS advantage in nonbilharzialsquamous cell bladder cancer. Those with clinically advanced disease continue to have a poor prognosis. However, OS does seem to have an improved prognosis compared to previous reports.
The effect of adjuvant chemotherapy for patients with adverse pathology after neoadjuvant chemotherapy for muscle invasive bladder cancer.
Authors: Parker William P. , Habermann Elizabeth B. , Day Courtney N. , Zaid Harras B. , Frank Igor , Thompson Robert Houston , Tollefson Matthew K. , Boorjian Stephen A. , Pagliaro Lance C. , Karnes Jeffrey 
Published: March 2017

367 Background: While neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) is recognized as the standard of care, the management of patients with locally advanced and/or nodal disease after NAC and radical cystectomy (RC) is not well defined. We sought to evaluate the association of adjuvant chemotherapy (AC) and overall survival (OS) among patients with adverse pathology after NAC and RC. Methods: The National Cancer Database was reviewed to identify patients with adverse pathology (pT3N0, pT4N0, or pTanyN1−3) at RC following NAC from 2006−2012. Patients were stratified by receipt of AC. Clinical and pathologic variables were abstracted. OS was the primary end−point and differences on the basis of AC were assessed by the Kaplan−Meier method and log−rank test. Multivariable Cox proportional hazards regression was used to assess the association of AC with OS controlling for age, sex, race, Charlson score, year of diagnosis, pathologic stage, and receipt of adjuvant radiotherapy. Results: Adverse pathology following NAC and RC was identified in 1,361 patients from 2006−2012, of whom 328 (24.1%) received AC. Staging was pT3N0 in 444 (32.6%), pT4N0 in 162 (11.9%), and pTanyN1−3 in 755 (55.5%). Median OS for the entire cohort was 22.9 months, which differed by pathologic stage: 34.6 months (pT3N0), 21.4 months (pT4N0), and 19.3 months (pTanyN1-3)(p < 0.01). No difference in OS was noted by receipt of AC in the overall cohort (median OS 24.6 months with AC vs 22.0 months without AC; p = 0.18), or when stratified by pathologic stage. On multivariable analysis, receipt of AC was not significantly associated with overall mortality (HR 0.86; 95%CI 0.74−1.01; p = 0.06) for all patients. When stratified by stage, AC was associated with a significantly decreased risk of mortality among patients with pT4N0 disease (HR 0.56; 95%CI 0.33−0.97; p = 0.04), but not pT3N0 or pTanyN1−3 (p > 0.05). Conclusions: Patients with adverse pathology at RC after NAC have a median OS of approximately 2 years. AC was not associated with improved survival, except in the subgroup with pT4N0 disease. Clinical trials with newer systemic therapies are warranted for patients in this setting.
The prognostic utility of hemoglobin and lymphocytopenia in bladder-sparing therapy.
Authors: Drumm Michael , Roberts Hannah Johnson , Shipley William U. , Niemierko Andrzej , Heney Niall M. , Kaufman Donald S. , Zietman Anthony L. , Efstathiou Jason A. 
Published: March 2017

370 Background: Many patients with bladder cancer are found to have laboratory derrangements such as anemia and lymphocytopenia prior to treatment, though their prognostic value is unknown. We examined pretreatment lab values and clinical outcomes in patients with muscle-invasive bladder cancer (MIBC) who underwent bladder sparing trimodality therapy (TMT). Methods: We performed a retrospective analysis of 181 patients with T2-T4a bladder cancer who underwent TMT between 2001 and 2013. Pretreatment absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR), and hemoglobin (Hgb) values were collected, and cut-off values were established to be 1.5*10^9/L, 3.12, and 12 g/dl, respectively. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were compared with Kaplan Meier survival probabilities and univariate and multivariate Cox regression analysis, controlling for gender, age, completeness of TURBT, response to TMT, cystectomy, clinical T stage, and hydronephrosis. Results: Median follow-up was 47 months. On univariate analysis, patients with a low pretreatment lymphocyte count had poorer OS (p = 0.03) than patients with a higher pretreatment lymphocyte count (5 year OS rates: 54% and 71%, respectively). Patients with pretreatment anemia had poorer OS (p = 0.001) and DSS (p < 0.001) than patients with a higher pretreatment hemoglobin count, (5 year OS rates: 39% and 65%; 5 year DSS rates: 39% and 72%, respectively). On multivariate analysis, pretreatment anemia was significantly associated with poorer OS (HR 2.58, 95% CI 1.36–4.90) and DSS (HR 3.23, 95% CI 1.62–6.43), whereas complete response to TMT was significantly associated with improved OS (HR 0.24, 95% CI 0.13–0.43) and DSS (HR 0.29, 95% CI 0.14–0.59). Complete response to TMT was significantly associated with improved DFS (HR 0.36, 95% CI 0.21–0.61), and a higher clinical T stage was associated with poorer DFS (HR 2.38, 95% CI 1.19–4.75). Conclusions: When adjusting for clinical factors, pretreatment anemia remained an independent predictor of overall and disease-specific survival following TMT. Further prospective validation of lab values and clinical outcomes in MIBC are needed.
Kent experience of radical chemoradiotherapy for muscle invasive bladder cancer.
Authors: Gough Jessica , Sridharan Mathini , Li Ruochen , Raman Rakesh , Edwards Albert , Clarke Amanda , Beesley Sharon , Taylor Henry J. H. , Lees Kathryn 
Published: March 2017

373 Background: The BC2001 trial in 2012 showed concurrent chemoradiotherapy to be the new standard of care for bladder preserving treatment of muscle invasive bladder cancer. Addition of concurrent MMC and infusional 5FU showed a relative risk reduction of 33% in locoregional recurrence (James ND, Hussain S, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.). This audit evaluates the experience across Kent in six hospitals adopting this protocol. Methods: 116 patients treated with radical radiotherapy for bladder cancer between January 2013 and December 2015 were retrospectively reviewed. 64 patients received radiotherapy alone due to contraindications to chemotherapy, performance status and patient choice. 52 patients received concurrent chemotherapy, the majority with 5FU/MMC and a subset with oral Capecitabine in place of infusional 5FU. Kaplan Meier and Log-Rank analysis of overall survival, local recurrence free survival and metastasis free survival were performed using SPSS. Results: Local recurrence free survival in the chemoradiotherapy group was 73% (95% CI 59-87%) compared to the radiotherapy group 61% (45-77) (p=0.27). There was a trend for greater metastasis free survival at 2 years, 63% (47-79) in the chemoradiotherapy group compared to 52% (38-66) in the radiotherapy group (p=0.21). Similarly, overall 2 year survival was 74% (60-88) and 59% (43-75) respectively (p=0.21). Conclusions: Our results showed a trend towards improved local control, distant control and increased overall survival in patients treated with concurrent chemoradiotherapy compared to radiotherapy alone. The differences did not meet statistical significance; however this was a small retrospective series with a relatively short median followup of 17.5 months. Treatment was well tolerated in our patient group. Overall, our data is in keeping with the results of the BC2001 trial (James ND, Hussain S, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.)
Identification of molecular biomarkers of cisplatin-based chemosensitivity in patients undergoing neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Shah Paras Hemant , Lee Annette , Zhu Xinhua , Bradley Thomas Paul , Vira Manish Arvind , Korsunsky Ilya , Shih Andrew , Yaskiv Oksana , Kozel Kozel 
Published: March 2017

374 Background: Although survival benefit of cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) has been demonstrated, a significant proportion of patients do not respond. Identification of chemoresponsive cohorts would avoid morbidity and delayed surgical intervention in patients unlikely to derive benefit. We evaluate the role of miRNA and mRNA expression profiles in initial TURBT specimens of patients who receive neoadjuvant chemotherapy prior to undergoing radical cystectomy. Differences in expression patterns between complete responders (pT0) and nonresponders (pT2 ≤ ) at time of cystectomy may help stratify patients being considered for neoadjuvant chemotherapy. Methods: FFPE tissue was isolated from initial TURBT specimens of patients with clinically localized MIBC treated with cisplatin-based neoadjuvant chemotherapy. Tissue from 9 patients with T2 ≤ disease was compared with specimen from 10 pT0 patients at time of cystectomy specimen. Differential expression of 754 miRNAs and mRNA was analyzed utilizing real time quantitative polymerase chain reaction. miRNA expression profiles were compared between complete responder and nonresponder groups. mRNA in tumor specimen was sequenced from both groups with 76 base pair paired-end reads using NextSeq technology. KEGG Pathway analyses helped identify differential gene expression between complete responders and nonresponders. Results: Significant upregulation of miRNA 1203, miRNA 1304, and miRNA 580 was observed nonresponders versus complete responders. KEGG pathway analysis revealed significant upregulation of the hsa03430 pathway, implicated in DNA mismatch repair, the hsa03420 pathway, implicated in nucleotide excision repair, and the hsa03410 pathway, involved in base excision repair, among pT0 patients. Conclusions: Differential miRNA and mRNA expression within the initial tumor specimen of patients with complete pathologic regression versus progression indicates a possible role in determining-neoadjuvant chemo-sensitivity.
Young patients with bladder cancer: Outcomes from the National Cancer Database.
Authors: Washington Samuel L , Meng Maxwell V. , Porten Sima P. 
Published: March 2017

380 Background: Bladder cancer (BC) affecting young patients is not well characterized but seems to be increasingly diagnosed. We aim to describe pathologic findings and BC outcomes in patients less than 40 years old using the National Cancer Database (NCDB), a US population based cohort capturing approximately 70% of newly diagnosed cancer cases. Methods: We identified 362,091 patients diagnosed with BC from 2004 to 2013. We compared demographic, clinical and pathologic information between those younger and older than 40 years. Univariate analysis was performed using Chi-square test for categorical variables and Independent Samples t-test for continuous variables. Multivariable Cox regression was used for survival analysis with hazard ratios (HR) and 95% confidence intervals (CI). Multivariable model was used to identify independent predictors of mortality (overall survival, OS). Results: 3,799 patients (1.1%) were 40 or younger with mean age of 34.5 years. Fewer young patients were women (25.2% vs 30.3%, p<0.001). More identified as nonwhite (11.6% vs 7.3%, p<0.001), had lower clinical T stage (cTa 51.4% vs 38.3%, cT1 13.3% vs 19.6; p<0.001), and longer median follow-up (46.4 months IQR 23.3-73.9 vs 35.3 months IQR 16.7-61.6). Age less than 40 (HR 0.3, 95% CI 0.2-0.3), chemotherapy (HR 0.9, 95% CI 0.9-0.9) and cystectomy (HR 0.8, 95% CI 0.8-0.9) were associated with decreased mortality when controlling for clinical characteristics (p<0.001). In sub-analysis of young patients with cystectomy, more had pT0 disease (20.3% vs 18.2%, p=0.005) with squamous cell carcinoma (13.6% vs 4%) and small cell (3.2% vs 1.6%) more prevalent (p<0.001). In adjusted models, squamous cell carcinoma (HR 1.1, 95% 1.1-1.2), small cell carcinoma (HR 1.5, 95% CI 1.4-1.7), RT (HR 1.2, 95% CI 1.!-1.3) and black ethnicity (HR 1.1, 95% CI 1.1-1.2) were independent predictors of worse OS. Conclusions: Younger patients with BC were more commonly non-white, men, and had low stage disease. In young patients undergoing cystectomy, squamous cell carcinoma, small cell carcinoma and black ethnicity were associated with worse OS. Further exploration in this younger patient cohort is needed to better characterize the optimal oncologic management for these patients.
Humanized mice (humice) carrying patient-derived xenograft (PDX) as a platform to develop immunotherapy in bladder cancer (BCa).
Authors: Pan Chong-xian , Shi Wei , Ma Ai-Hong , Zhang Hongyong , Lara Primo , Keck James G. , Palucka Karolina , Airhart Susan D. , deVere White Ralph 
Published: March 2017

381 Background: Immunotherapy with anti-programmed cell death 1 (PD1) or PD ligand 1 (PD-L1) antibody has emerged as a promising therapeutic modality, but has a response rate of approximately 20% in BCa. There are various drawbacks associated with current animal models. The objective of this study is to establish and characterize humice carrying PDXs in which both the immune cells and BCa cells are derived from humans. Methods: NOD-scid IL2Rgammanull or NSG, mice received CD34+ hematopoietic progenitor cells (HPC) cells i.v. after whole body radiation. PDXs were established through direct implantation of human BCa clinical specimens into NSG mice. Immune cell subpopulations were analyzed through flow cytometry analysis. Humice carrying HLA-unmatched PDXs were treated with an anti-PD1 antibody pemborlizumab (pembro) or in combination with a BKT/ITK inhibitor ibrutinib to determine the anti-tumor efficacy and toxicity. Results: PDXs retained the morphology fidelity and 92-97% of genetic alterations of parental patient cancers. Of the first 8 PDXs tested, 3 had high PD-L1 ( > 10 FPKM) as determined by RNA-seq which was further confirmed with flow cytometry analysis. Major human immune cell sub-populations were reconstituted in humice. No xenograft versus host disease was observed before pembro treatment. In humice with HPC donor 6466, pembro significantly inhibited tumor growth (p = 0.0016 at Day 29) of PDX BL293, but had no effect in another PDX BL440 with the same HPC donor 6466, or with the same PDX BL293 but with a different HPC donor 912. In another set of humice (HPC donor 710) carrying PDX BL293, pembro alone inhibited tumor growth. However, addition of ibrutinib did not potentiate the efficacy of pembro, but increased toxicity. Tumor regression with pembro treatment was associated with decrease of CD4+PD1+, CD8+PD1+ cells at peripheral blood and increased CD45+ and CD8+ cells in PDXs. Conclusions: Humice carrying PDXs reconstitute with human immune system, and can potentially be used to screen for effective immunotherapeutic agents or combinations, and to study resistant mechanisms.