bluuebunny/crossref_metadata_2025 huggingface dataset:
Sarcopenia as a useful predictor of postoperative complications following radical cystectomy: An assessment of preoperative CT scans.
Authors: Hennig Martin Jp , Hupe Marie C , Hensen Bennet , Jansen Max Clemens , Kramer Mario W , Kuczyk Markus A , Merseburger Axel Stuart
Published: March 2017

351

Background: Muscle-invasive urothelial carcinoma is usually treated with radical cystectomy (RC). However, patients face a relevant risk of postoperative complications on variable factors. Recent reports described that sarcopenia, which is defined by a loss of sceletal muscle body composition, may enhance risk stratification. Methods: Our retrospective study includes 200 patients (154 men, 46 women, mean age: 67.9 years) which were treated with RC between 2005 and 2014. Median follow-up time was 26 months. Computed tomography (CT) scans were performed within 60 days prior to surgery. Lumbar skeletal muscle index (SMI) were measured with MeVisLab 2.7 by manually segmentation of preoperative CTs. The fat mass index (FMI) was calculated based on the same CT slides. Cut off points were developed for men and women separately. Additionally, short-, mid- and long-term complications were assessed using the Clavien-Dindo classification. Results: SMI (cm2/m2), FMI (kg/m2) and BMI (kg/m2) for men were calculated with mean scores of 52.8, 9.6 and 26.7, respectively. The corresponding calculated means for women were 38.9, 10.0 and 26.1. The SMI for short- and mid-term complications was statistically significant (p < 0.01) when applied on patients with a BMI over 25 kg/m2. Using Kaplan-Meier plots none of the other markers (BMI and FMI) correlated with complications or overall survival (OS). Conclusions: The presence of sarcopenia assessed by CT may improve risk stratification in patients undergoing radical cystectomy. BMI and FMI may not be used in risk stratification models, even though further validation for subgroups is needed. Future research is needed to validate the current findings. Noninvasive and semiautomatic calculation of SMI in preoperative CT scans may improve risk stratification in patients undergoing radical cystectomy and thus could reduce morbidity and mortality.
Association of preoperative neutrophil-to-lymphocyte ratio with survival outcomes in patients undergoing radical cystectomy, regardless of neoadjuvant chemotherapy status.
Authors: Kukreja Janet Baack , Podolnick Jason M , Wang Xuemei , Chen Hsiang-Chun , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul
Published: March 2017

352

Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial bladder carcinoma (BC). Prior studies have determined inclusion based on neoadjuvant chemotherapy (NAC) status. This study aimed to evaluate pre-operative NLR in a large cohort without exclusion as a predictor of long-term outcomes in patients undergoing RC for BC. Methods: A retrospective cohort study was performed of 1243 patients undergoing RC between 2000 and 2011. NLR was summarized using descriptive statistics. Univariate classification and regression trees analysis (CART) was applied to identify subgroups of patients using pre-surgery NLR as the covariate and overall survival (OS) or disease specific survival (DSS) as the outcome of interest. The probabilities of OS and DSS were estimated using the Kaplan-Meier method. Results: The median follow-up time among survivors was 7 years. 863 (69%) patients died and 380 (31%) were alive at last follow-up. The median OS was 5.2 years (95% CI: 4.9-5.5 years). Using CART analysis, the strongest association with OS was the cutoff point 3.09. 767 (62%) patients had pre-surgery NLR < 3.09 and 475 (38%) had pre-surgery NLR ≥ 3.09. The overall survival was found to be significantly associated with NLR < 3.09 vs. ≥ 3.09 (p < 0.001). The median OS for patients with NLR < 3.09 and ≥ 3.09 was 5.9 years (95% CI: 5.3-6.3 years) and 4.2 years (95%:3.3-4.7 years), respectively. Patients with NLR < 3.09 and ≥ 3.09 had 5-year OS of 56% and 44%, respectively. DSS was found to be significantly associated with NLR ≥ 3.09 vs. < 3.09 (p < 0.001). The median DSS for patients with pre-surgery NLR < 3.09 and ≥ 3.09 were 15.6 years and 7.5 years, respectively. Conclusions: The NLR significantly predicts OS and DSS in RC patients. NLR should be taken into consideration as NAC and adjuvant treatments are considered in BC patients to help improve survival.
Survival for patients with residual tumor at radical cystectomy following chemotherapy: A matched analysis to cystectomy-only patients.
Authors: Bhindi Bimal , Frank Igor , Mason Ross , Tarrell Robert F. , Thapa Prabin , Cheville John C. , Costello Brian Addis , Pagliaro Lance C. , Karnes Jeffrey , Thompson Robert Houston , Tollefson Matthew K. , Boorjian Stephen A.
Published: March 2017

355

Background: While neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) improves survival compared to RC alone for urothelial carcinoma of the bladder (UCB), the bulk of this survival benefit has been attributed to patients who achieve ypT0 status at RC. The implications of having residual UCB (rUCB) at RC after NAC are less clear. As such, we evaluated whether the outcomes for patients with rUCB after NAC differ from stage-matched RC patients who did not receive NAC. Methods: Patients undergoing RC for UCB between 1981-2010 at Mayo Clinic were identified. All RC pathology was re-reviewed by a single genitourinary pathologist. Patients who received NAC were matched 1:2 to patients not exposed to NAC based on pT and pN-stage, margin status, and year of RC. Kaplan Meier and Cox regression analyses were used to evaluate the associations between NAC and cancer-specific (CSS) and overall survival (OS), stratified by presence of rUCB (i.e. (y)pT0N0 and non-(y)pT0N0). Results: We matched 111 patients who underwent NAC + RC to 222 RC-alone patients. Median age was 68 years (IQR 60,74); 59 (18%) were female. Median follow-up among survivors was 7.2 years (IQR 6,16). A total of 248 patients died; 148 died from UCB. In patients without rUCB at RC, there were no differences in 5-yr CSS (86% vs. 90%, p=0.85) or OS (82% vs. 84%, p=0.46) between patients who did and did not receive NAC. Moreover, on multivariable analysis, NAC exposure was not associated with CSS (HR=1.0; 95%CI 0.3-3.1; p=0.9) or OS (HR=0.9; 95%CI 0.4-1.9; p=0.8) in this subgroup. Among patients with rUCB, receipt of NAC was associated with significantly worse 5-yr CSS (32% vs. 56%, p<0.001) and OS (25% vs. 48%, p<0.001). NAC exposure remained independently associated with worse CSS (HR=2.2; 95%CI 1.6-3.1; p<0.001) and OS (HR=2.0; 95%CI 1.5-2.7; p<0.001) among these patients. Conclusions: While patients who achieve a complete response to NAC have excellent survival outcomes, patients with residual UCB at RC after NAC have a worse prognosis compared to stage-matched RC patients not exposed to NAC. Such patients should be considered for enrolment in novel adjuvant therapy trials.
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.
Evaluation of the clinical activity of ipilimumab (IPI) plus nivolumab (NIVO) in patients (pts) with NIVO-refractory metastatic urothelial cancer (UC).
Authors: Callahan Margaret K. , Kania Brooke Elizabeth , Iyer Gopa , Clement Jessica Mary , Funt Samuel , McCoy Asia S. , Hettich Grace , Ziv Etay , Bluth Mark J. , Wong Phillip , Wolchok Jedd D. , Bajorin Dean F. , Rosenberg Jonathan E.
Published: March 2017

384

Background: Programmed cell death –1 (PD-1) and its ligand (PD-L1) serve as checkpoints that regulate the interaction between the immune system and tumors. Antibodies blocking PD-1 or PD-L1 enhance antitumor activity in pts with UC. NIVO, a PD-1 blocking antibody, has clinical activity in UC as a single agent. IPI, an antibody blocking the checkpoint molecule CTLA-4, has demonstrated biologic activity in UC. Dual checkpoint blockade with both NIVO and IPI also has clinical activity in UC, but has not been systematically studied in NIVO-refractory UC. We sought to evaluate whether the addition of IPI to NIVO is feasible and clinically beneficial in pts whose UC is refractory to single agent NIVO. Methods: Forty pts with advanced or metastatic UC were treated with NIVO (3 mg/kg every 2 weeks) as part of a single arm, IRB-approved, investigator initiated study (NCT02553642). The study offered the option of treatment with the combination of IPI (1 mg/kg) and NIVO (3 mg/kg) for pts who had confirmed progression after treatment with NIVO monotherapy. The combination was dosed once every 3 weeks for 4 doses and followed by NIVO monotherapy. Pts were monitored for response and toxicity. Results: Ten pts who were refractory to NIVO monotherapy were treated with the combination of IPI and NIVO. There was a modest increase in the frequency of toxicities associated with the combination, compared to NIVO alone. One pt developed grade 3 diarrhea after treatment with the combination. No grade 3/4 toxicities were observed in pts treated with NIVO monotherapy. One pt achieved a confirmed partial response. Three additional pts achieved stable disease after documented progression. Pharmacodynamic changes in peripheral blood immune cells were monitored during treatment with NIVO monotherapy and combination therapy. Conclusions: The combination of IPI and NIVO is well tolerated and may have clinical activity in pts with UC who fail to respond to PD-1 blockade. Further studies to evaluate the magnitude of clinical activity and predictors of response for this combination are needed. Clinical trial information: NCT02553642.
Patient selection using novel RNA-based approaches: Early experience from a phase I study with the pan-FGFR inhibitor BAY 1163877 in patients with urothelial bladder cancer.
Authors: Joerger Markus , Schuler Martin H. , Cassier Philippe Alexandre , Hildebrandt Sandra , Behre Simone , Helmbrecht Corinna , Kerpen Stephanie , Zielinski Dirk , Ince Stuart , Ocker Matthias , Ellinghaus Peter
Published: March 2017

386

Background: FGFRs play a role in a variety of malignancies, including urothelial bladder cancer (UBC). Whereas genetic alterations of FGFRs in UBC are known, non-genetic and epigenetic activation of FGFR gene expression have also been described. BAY 1163877 is an oral inhibitor of FGFRs 1-3 with antitumor activity in FGFR mRNA overexpressing xenograft models not limited to DNA alterations. We report the results from a phase I expansion cohort in UBC patients pre-screened for treatment with BAY 1163877 based on FGFR1-3 mRNA overexpression and/or activating mutations in the FGFR3 gene. Methods: FGFR mRNA levels were assessed in paraffin-embedded archival or fresh biopsy specimens by RNAscope and NanoString technology and activating mutations by RT-PCR-based mutation assay. Tumor response to treatment was assessed by RECIST, v1.1. Adverse events were assessed using CTCAE v4.03 criteria. Results: A total of 80 patients from multiple indications were enrolled in the phase I study; 800 mg BID was established as the recommended phase 2 dose. Sixty seven UBC patients were screened, with 31 tumor biopsies (46%) determined to overexpress FGFR mRNA: 2 patients each with FGFR1 and FGFR2, and 27 patients with FGFR3. Of the 27 patients with FGFR3 mRNA overexpression, 5 had in parallel an activating mutation in FGFR3 gene. Eight UBC patients met eligibility criteria and entered treatment; all had elevated FGFR3 mRNA expression and 4 had alterations in FGFR3 DNA (3 mutations and 1 translocation). Seven patients (87.5%) had tumor shrinkage in target lesions as best response, with 3/8 partial responses (PR; 37.5%). One patient with a PR presented with elevated FGFR3 mRNA without evidence of aberrant DNA. BAY 1163877 was generally well tolerated and AEs manageable with dose modification. The most common AEs in the overall population were increased phosphorus (66% all grade, 1 grade-3 event) and diarrhea (33% all grade, 2 grade-3 events). Conclusions: Selection of patients for treatment with BAY 1163877 based on FGFR mRNA expression levels in archival tissue was feasible. BAY 1163877 had a favorable safety profile and promising anti-tumor activity in UBC patients. Clinical trial information: NCT01976741.
Neoadjuvant chemotherapy for elderly patients with locally advanced disease: Are we doing enough?
Authors: Correa Andres , Handorf Elizabeth , Joshi Shreyas , Ristau Benjamin T. , Haifler Miki , Kutikov Alexander , Greenberg Richard E. , Chen David , Uzzo Robert G. , Viterbo Rosalia , Geynisman Daniel M. , Smaldone Marc C.
Published: March 2017

389

Background: The administration of neoadjuvant chemotherapy (NAC) for patients with muscle invasive urothelial carcinoma improves overall survival. Recent reports have shown that the survival benefit may be greater in patients with locally advanced disease. Our objective was to assess the utilization of NAC by stage and age using a large national tumor registry. Methods: Patients who underwent radical cystectomy for cT2-4 N0-1 M0 urothelial carcinoma diagnosed between 2003-2012 were selected from the National Cancer Data Base. We excluded those with planned radiation therapy or who received palliative care. A multivariate logistic regression analysis was constructed to identify factors that affected administration of NAC. Covariates included were clinical stage, age, race, sex, insurance status, income, Charlson index, clinical stage group, demographic location, facility location, and diagnosis year. We also used interaction terms in the regression model to determine if stage effects differed by age group. Results: A total of 16,248 patients met inclusion criteria for the study. The use of NAC increased over the study period with 6% of eligible patients receiving NAC in 2003 vs. 27.7% in 2012 (p < 0.001).Increasing utilization of NAC was noted with increasing stage (cT2N0: 15.7%; cT3N0: 19.8%; cT4N0/TanyN1: 20.9%, p < 0.001) and decreasing NAC utilization was noted with increasing age ( < 65 years: 18.5%; 65-74 years: 18.5%; ≥ 75 years: 9.0%, p < 0.001). Following adjustment, increasing clinical stage was associated with an increase in the administration of NAC, (cT3N0 OR 1.46 [CI 1.24-1.71]; T4/TanyN1 OR 1.88 [CI 1.62-2.18]) compared to cT2 disease. In comparison, increasing age (age 65-74 years OR 0.78 (CI 0.68-0.88]; age ≥ 75 years OR 0.37 [CI 0.33-0.43]) was associated with decreased utilization of NAC compared to patients < 65 years. On interaction analysis the effect of higher stage on the likelihood of receiving NAC was attenuated in older patients ( ≥ 75 years). Conclusions: The administration NAC has increased over the last 10 years and is more likely to be given to patients with locally advanced disease or early nodal stage. However, this trend is substantially attenuated in older patients ( ≥ 75 years).
Cisplatin-based neoadjuvant chemotherapy (NAC) in bladder cancer patients (Pts) with borderline renal function: Implications for clinical practice.
Authors: Koshkin Vadim S. , Barata Pedro C. , Zahoor Haris , Rybicki Lisa A. , Emamekhoo Hamid , Almassi Nima , Tullio Katherine , Redden Alicia M , Fergany Amr Farouk , Kaouk Jihad , Haber Georges-Pascal , Beach Jennifer , Martin Allison , Allman Kimberly D , Garcia Jorge A. , Gilligan Timothy D. , Rini Brian I. , Grivas Petros
Published: March 2017

390

Background: Cisplatin-based NAC prior to cystectomy is a standard of care in muscle-invasive bladder cancer (MIBC). There are limited data for pts with borderline glomerular filtration rate (GFR) who get cisplatin-based NAC. Methods: A retrospective review of pts who received cisplatin-based NAC at Cleveland Clinic (2005-2016) was done. Pts with pre-NAC GFR of 40-59 mL/min by either CG or MDRD formula (low GFR group; n = 17) were compared to pts with GFR ≥ 60 (nl GFR group; n = 74) for treatment-related toxicities and outcomes, such as pathologic complete (pCR, pT0N0) and partial response (pPR, < pT2N0), overall survival (OS) and recurrence-free survival (RFS). Comparisons were made using Fisher’s exact, Wilcoxon, or log-rank tests. Results: Pts with low GFR were older (median age 69 vs 64, p = .02) with worse PS (44% vs 20% ECOG > 0, p < .05). Gender, race, hydronephrosis rates and TURBT features (stage, grade, LVI, CIS) did not differ. For NAC, 64 pts got Gem/Cis (49 normal GFR, 15 low GFR), 23 got MVAC (22 normal GFR, 1 low GFR), 4 got other. Low GFR pts were less likely to get MVAC (6% vs 30%, p = .08) and more likely to get split-dose cisplatin (38% vs 18%, p = .10) and have NAC modified (delayed, dose reduced or stopped) (69% vs 36%, p = .02). 4/17 pts (24%) with low GFR and 9/73 (12%) with normal GFR did not complete all planned NAC cycles (p = .26). Hematologic toxicity caused most dose delays but renal toxicity was the most common cause of NAC stoppage (4/9 normal GFR, 3/4 low GFR). NAC cycles completed (median 3 / group) and G-CSF use (31/61 normal GFR, 3/9 low GFR) were comparable. No difference was noted in time to cystectomy (mean 107 days for normal vs 103 days for low GFR from NAC start), surgical complications, length of stay, and either post-NAC or post-cystectomy GFR decline from baseline. Combined pathologic response (pCR/pPR) was higher in normal GFR pts (50% vs 18%, p = .02). OS and RFS at 2 years were 89% and 79% for normal GFR and 78% and 58% for low GFR. Conclusions: Low GFR pts were older with worse PS, had more NAC modifications, lower pCR/pPR and trend for shorter OS & RFS, but most completed planned NAC cycles. For very carefully selected pts with GFR 40-59, cisplatin-based NAC is a treatment option.
Tumor mutation burden to predict progression in high-risk non-muscle invasive bladder cancer.
Authors: Meeks Joshua , Carneiro Benedito A. , Pai Sachin Gopalkrishn , Oberlin Daniel , Rademaker Alfred , Fedorchak Kyle , Balasubramanian Sohail , Elvin Julia Andrea , Beaubier Nike , Giles Francis J.
Published: March 2017

397

Background: The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. Methods: DNA was extracted from formalin-fixed paraffin-embedded sections of tumor from 25 patients with HR-NMIBC (23 with T1HG; 3 with TaHG and carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) (“progressors”). Fifteen patients had no progression (“non-progressors”). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. Results: We identified no difference in the frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of mutations and deletions causing loss of function of CDKN2A and CDKN2B was identified in tumors at progression (37%) compared to non-progressors (6%) (p=0.10). We found a significant decrease in total mutational burden (TMB) comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p=0.02). This association suggests more advanced tumors have decreased neoantigen burden and may potentially explain the mechanism of BCG response in non-progressors. Conclusions: TMB was significantly greater in non-progressors compared to progressors. We found no novel genetic drivers in tumors that progressed and HR-NMIBC had many genetic features similar to metastatic BC. The loss of CDKN2A appears to occur late in the process of invasion of BC and may represent an important step in progression. Further research is necessary to evaluate loss of CDKN2A as a biomarker for progression of NMIBC.
111: A single-arm trial evaluating one cycle of BEP as adjuvant chemotherapy in high-risk, stage 1 non-seminomatous or combined germ cell tumors of the testis (NSGCTT).
Authors: Huddart Robert Anthony , Joffe Johnathan K. , White Jeff D. , Hutton Paul , Lewis Rebecca , Mazhar Danish , Osborne Colin , Piercy Deborah , Wiley Laura , Witts Stephanie , Maynard Lauren , Hall Emma , Cullen Michael H. ,   on behalf of the 111 Trial Management Group
Published: March 2017

400

Background: The standard post-orchiectomy treatment for UK patients (pts.) presenting with high-risk stage 1 NSGCTT is 2 cycles of bleomycin, etoposide (360mg/m2) & cisplatin (BE360P) chemotherapy or surveillance with BEPx3 at recurrence. 111 (CRUK/09/011) investigates whether BE500P x1 would achieve recurrence rates similar to BE360P x2. Methods: Pts aged ≥16 yrs post-orchiectomy for vascular invasion positive stage 1 NSGCTT or combined seminoma + NSGCT, with normalised tumour markers, received 1 cycle of bleomycin30000IU day 1, 8 & 15, etoposide165mg/m2 day 1, 2 & 3, &cisplatin50mg/m2day 1 & 2. All pts received a prophylactic antibacterial & GCSF. Pts were assessed for tumour markers q2m, q3m, q4m in years (yrs) 1, 2, 3, respectively and q6m in yrs 4 & 5. CT scan of chest, abdo and pelvis was performed at 6, 12, 24 & 60months (m) with chest x-ray at other visits. Toxicity was assessed using NCI CTCAE v3. Recurrences were independently reviewed. A sample size of 236 pts excludes a 2-yr recurrence rate of ≥5% if ≤6 recurrences were observed (80% power, 5% α). Results: Between 18/2/2010 and 31/7/2014 246 pts. were recruited at 33 UK centres; 54% with NSGCTT, 46% with combined GCT. Median follow-up was 39.1m (IQR 30.0-50.8). Four patients had malignant recurrences at 5, 8, 12 and 27m. 2 yr recurrence rate in 236 treated pts = 1.3% (95% CI: 0.4 to 4.0%). All 4 pts with recurrences were treated with 2ndline chemotherapy +/- surgery, 3 are alive and free from disease, 1 died at 9m with refractory disease. In addition there were 3 non-malignant recurrences at 7, 10 and 13m with teratoma differentiated in retroperitoneal nodes (3, 4 and 4.4cm). All these pts are disease-free post RPLND surgery. 41% pts had grade 3-4 CTCAE at end of treatment (neutropenia: 31% and febrile neutropenia: 7%). The 2 yr overall survival is 99.2% (95% CI: 96.7, 99.8%). Conclusions: BE500P is safely deliverable & 2 yr recurrence rate is similar to that seen with 2 cycles BE360P. The adoption of BE500P x1 as standard would reduce overall exposure to chemotherapy in this young pt population. 111 is the biggest formal, prospective trial to date investigating adjuvant BEPx1 in high-risk stage 1 NSGCTT. Clinical trial information: ISRCTN37875250.