bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of immune checkpoint inhibitors (ICIs) in rare histological variants of bladder cancer.
Authors: Philip Errol James , Wright Francis , Kim Daniel Myung , Kwon Daniel , Ho Hansen , Ho Son , Cheung Edna , Chan Emily , Porten Sima P. , Wong Anthony C. , Borno Hala , Desai Arpita , Chou Jonathan , Oh David Yoonsuk , Aggarwal Rahul Raj , Fong Lawrence , Small Eric Jay , Friedlander Terence W. , Koshkin Vadim S 
Published: February 2020

502 Background: ICIs are effective agents in metastatic urothelial carcinoma in both platinum-refractory and frontline settings. Responses in patients (pts) with non-urothelial histological variants are not well defined. Methods: We undertook a retrospective analysis of pts with metastatic bladder cancer treated with ICI monotherapy. Pts were identified as having a variant histology if any non-urothelial component was present. Fisher’s exact test was used to assess differences in ORR by histology. Results: Between 12/2014 and 10/2019, 102 pts received ICI monotherapy, of whom 93 were evaluable for response and 33 had variant histology. Median age was 70 yrs, 66% were male, 50% received prior platinum-based chemotherapy. Most received pembrolizumab (66%) or atezolizumab (33%). ORR in the overall cohort was 26% (15% PR, 11% CR), with 12% having SD. Histology breakdown and responses are shown in Table. Although twice as many responses were seen in urothelial pts as in pts with variant histologies (ORR 31% vs 15%), this difference was non-significant (p = 0.14). Conclusions: In this large single-institution cohort, ORR in a heterogeneous population of bladder cancer pts was consistent with data previously reported in clinical trials. Pts with variant histologies had numerically lower responses relative to pure urothelial histology, but this difference was not statistically significant. Clinical benefit to ICIs was seen across multiple variant histologies suggesting potential efficacy in this patient population that should be confirmed prospectively.[Table: see text]
Safety and efficacy of neoadjuvant chemotherapy (NAC) with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) in patients (pts) with muscle invasive bladder cancer (MIBC) as a function of age.
Authors: Zibelman Matthew R. , Lewis Bianca , Ross Eric A. , Anari Fern , Ghatalia Pooja , Plimack Elizabeth R. , Geynisman Daniel M. 
Published: February 2020

506 Background: NAC improves survival in pts with MIBC eligible to receive cisplatin-based chemotherapy. Prospective data supports the use of aMVAC, however concerns about toxicity limits usage compared to gemcitabine and cisplatin, especially in the elderly. We investigated the safety and efficacy of aMVAC as a function of age. Methods: We conducted a retrospective analysis of pts with MIBC at Fox Chase Cancer Center who received NAC with aMVAC from 2008-2017. Pts were excluded for non-urothelial histology, non-muscle-invasive or primary upper tract disease, or if final pathology was not available. Clinicopathologic variables were extracted from charts and pts were grouped into 3 cohorts by age ( < 65, 65-74, ≥75). Associations between age group (gp) and categorical/continuous factors were evaluated using Fisher’s exact/Wilcoxon rank sum tests. Results: A total of 90 pts ( < 65: 40; 65-74: 28; ≥75: 22) were evaluable for safety and 84 for efficacy. The majority of pts were male (72%), PS 0 ( < 65: 85%; 65-74: 85%; ≥75: 68%) and Caucasian (90%). Baseline clinical staging was cT2 in 50%, cT3 in 27% and > cT3 in 14%, with 9% lacking clinical staging. Mean number of aMVAC cycles delivered was numerically similar between age gps, though statistically different (3.1 v 2.8 v 2.6; p = 0.01). There were no statistically significant differences in dose reductions, treatment interruptions, or time to surgery (10.7 v 10.7 v 10.1 wks, p = 0.91) by age. Grade ≥3 AEs were most frequent in the youngest age gp (14.4% v 2.2% v 8.9%, p = 0.018). Split-dose cisplatin was increasingly used in advanced age (2.5% v 17.9% v 31.8%, p = 0.003). Although glomerular filtration rate (GFR) at baseline inversely correlated with age (105 v 93 v 63 ml/min, p < 0.0001), there was no difference in % GFR decline at 90 days or 1 year. The downstaging rate to < pT2N0 disease was similar in all age gps (41.0% v 29.6% v 38.9%; p = 0.41). At median follow-up of 20 months, recurrence rates were 30.0% v 25.9% v 28.6% (p = 0.95). Conclusions: NAC with aMVAC yields similar safety and efficacy outcomes regardless of age, thus age should not be a factor in determining treatment eligibility.
Results after two years of follow up after intravesical thermochemotherapy with heated mitomycin 40 in patients with high-risk superficial bladder cancer.
Authors: Voegeli Thomas Alexander , Frank Eric , Bach Christian , Nzeh Catejan 
Published: February 2020

512 Background: Standard management of high risk TCC is either BCG or radical cystectomy, alternative treatment options are limited. It is known that the anti-tumor effect of heated mitomycin is 10 fold higher than at room temperature, which is the standard of intravesical therapy. We herein report the first 2 year follow up (FU) after intravesical therapy with heated mitomycin in a cohort of patients with high risk superficial bladder cancer (TCC). Methods: Treatment was performed for 1 hour with machine bladder irrigation (COMBAT) which maintaines temperature of mitomycin (40 mg) exactly at 43 C. Patients underwent therapy with a 6 week course of weekly treatment and were than followed by cystoscopy every 3 month and if necessary biopsy. Results: We identified 62 patients out of a total group of 108 patients who met the inclusion criteria for high risk TCC according to the EAU Guidelines and who got the complete 6 courses of treatment. 2 were lost of follow up, 1 died due to cardiac problems and 1 from metastatic prostate carcinoma. The remaining 58 patients had a mean FU of 26 month (16-54 m) and included 20 non-responders to BCG. 48/58 patients had CIS or pT1 Tumors or both, 10 patients had pTa+CIS. There were 5 recurrences, all superficial stage pTa, one in the rigth ureter, all could be managed without cystectomy. 8 patients had progressive or recurrent CIS/pT1 or were progressive to pT2 after therapy and underwent cystectomy. Conclusions: In this high risk cohort of 58 patients with a high rate of BCG non-responders only 8 patients had to undergo cystectomy during a 2 year follow up. Intravesical therapy with heated mitomycin is safe and well tolerated and may be an additional alternative treatment before cystectomy is performed in high risk patients with high risk TCC or BCG non responders.
Prospective trial of adjuvant therapy after radical cystectomy for locally advanced bladder cancer: Analysis of the squamous cell carcinoma subgroup.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Zaghloul Tarek , Abdalla Ahmed , William Hany , Khaled Hussein Mustafa , Hwang Wei-Ting , Baumann Brian Christopher 
Published: February 2020

524 Background: The role of adjuvant therapy after radical cystectomy (RC) is not well-defined for squamous cell carcinoma (SqCC) of the bladder. Several studies suggest limited efficacy for chemo while adjuvant RT improved disease-free survival (DFS) vs. observation in a previous trial. In this study, we report a post-hoc subgroup analysis of SqCC to compare adjuvant therapies. We hypothesized that adjuvant RT would improve DFS vs. chemo for locally advanced bladder cancer (LABC) (≥pT3N0-N+). Methods: A randomized phase III trial was opened to compare adjuvant RT vs. sandwich chemo+RT after RC for LABC at the NCI in Cairo. A 3rd arm, adjuvant chemo, was added later. Bladder cancer patients ≤70 y/o with ≥1 of the following (pT3b/pT4a, grade 3, or pN+) with negative margins after RC were eligible. RT was delivered to the pelvis with 3D conformal RT (45Gy in 1.5Gy BID). Chemo+RT included 2 cycles of gemcitabine/cisplatin before & after RT. Chemo alone included gem/cis x 4. Primary & secondary endpoints were DFS and overall survival (OS). Results: 198 patients were enrolled. 82 (41%) had SqCC & 77 had ≥pT3N0-N+ disease and were analyzed (34 RT, 27 chemo+RT, & 16 chemo). Median age was 53. Median F/U was 20 months (1-127 months). The RT vs chemo arms were well-balanced except for number of nodes removed (mean 12 vs. 9, p=0.05). On univariable analysis, RT was not significantly associated with DFS [HR 0.56 (95%CI 0.26-1.21), p=0.14]. On multivariable analysis, only pN+ was significant. 2-yr DFS was 60% for RT & 43% for chemo (log-rank p=0.13). OS was improved with RT (2-yr OS 71% vs. 43%, p=0.04). There was one death during treatment (chemo-related). There was no significant difference in DFS or OS for RT vs. chemo+RT with 2-yr DFS of 59% & 55% (p=0.65) & 2-yr OS of 67% & 74% (p=0.16). Conclusions: On post-hoc analysis, RT for locally advanced bladder SqCC was associated with significantly improved OS vs. adjuvant chemo. We hypothesize that the inferior OS with chemo was due to increased toxicity & limited efficacy. There was no difference in outcomes for RT vs. chemo+RT. Adjuvant RT should be a standard option for ≥pT3 SqCC of the bladder after RC. Alternative chemo agents for SqCC should be explored. Clinical trial information: NCT01734798.
Smoking status and PD-L1 mRNA-expression as a predictor of response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.
Authors: Reike Moritz , Juette Hendrik , Wirtz Ralph , Erben Philipp , Tully Karl , Eckstein Markus , Weyerer Veronika , Hartmann Arndt , Kriegmair Maximilian , Wezel Felix , Bolenz Christian , Tannapfel Andrea , Noldus Joachim , Roghmann Florian 
Published: February 2020

530 Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Patients with a pathological complete response (pCR) usually have the best prognosis. In the literature, impaired response to immune checkpoint therapy has been reported in active smokers. The aim of our study was to examine the association of smoking status with pCR at RC after NAC. Moreover, we investigated the interaction of smoking status and Programmed Death Ligand 1 (PD-L1) mRNA expression at transurethral resection (TUR) and pCR prediction at RC after NAC. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR PD-L1 mRNA expression was measured in 40-∆Ct values and normalized against the control gene CALM2. Smoking status was defined as never, former and active. After NAC, RC was performed and the specimens were evaluated for pCR, defined as ypT0N0M0. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. Regarding smoking status 11/49 (22%) were never, 17/49 (35%) were former and 21/49 (43%) were active smokers. After NAC, 17/49 patients (35%) had a pCR. Never/former smokers did not show a higher rate of pCR compared to active smokers (43%vs.24%, p=0.16). Comparing smoking status (never/former vs. active smokers) within the subgroup showing high PD-L1 expression (≥32.1∆Ct), a higher rate of pCR was found in never/former smokers (58% vs. 25%, p=0.047). Conclusions: Never and former smokers with MIBC that show high PD-L1 mRNA expression patterns are more likely to show pCR at RC after NAC. Smoking cessation is important for the management of MIBC patients undergoing NAC and RC.
The clinical prognostic impact of APOBEC3B protein expression in metastatic urothelial carcinoma.
Authors: Kim Hyunho , Kim In-Ho , Yim Kwangil 
Published: February 2020

544 Background: APOBEC3 enzymes function as a carcinogenic mutagens resulting in substitution of Cytosine to Thymine or Guanine in tCw motif. Mutation signature in urothelial (UC) carcinoma is mediated by APOBEC3 more than smoking which is well known as a risk factor. This study aimed to explore the association of APOBEC3 expression with survival in metastatic UC (mUC). Methods: We examined 94 patients treated with gemcitabine plus platinum chemotherapy for mUC. APOBEC3A and 3B protein expression was measured using immunohistochemistry from archived formalin-fixed paraffin-embedded tissue which was obtained before chemotherapy. Immunohistochemistry results were evaluated by H-score. The cutoff levels of APOBEC3A and 3B expression were calculated with time dependent ROC analysis. Results: APOBEC3B high expression exhibited longer overall survival (OS) and progression-free survival (PFS) than low expression (median OS: 16 months vs 9 months, p=0.032; median PFS: 7 months vs 4 months, p=0.017). APOBEC3A high expression was associated with longer OS (median OS: 13 months vs 9 months, p=0.036; median PFS: 6 months vs 4 months, p=0.405). Disease control (CR/PR/SD) rate (DCR) was higher in APOBEC3B high group than low group (DCR, 79.4% and 57.1%, respectively, p=0.045). Mean H-score of APOBEC3B was higher in disease control group than progressive disease group (mean H-score, 125.3 vs 101.3, p=0.029). APOBEC3A expression was not correlated with chemotherapy response. There was not a significant correlation between APOBEC3A and APOBEC3B (Spearman correlation coefficient=0.111, p=0.319). Conclusions: mUC with APOBEC3B high expression may be associated with better response from gemcitabine plus platinum chemotherapy and longer overall survival. Further functional studies are warranted to clarify the clinical significance of APOBEC3B protein expression in mUC.
Landscape of cyclin pathway genomic alterations across 7,207 non-prostate genitourinary tumors.
Authors: Fontes Jardim Denis Leonardo , Millis Sherri Z. , Woo Michele Sue-Ann , Ross Jeffrey S. , Ali Siraj Mahamed , Kurzrock Razelle 
Published: February 2020

549 Background: Cyclin pathway genomic alterations can be a possible therapeutic target as well as a resistance mechanism for therapy. We describe the landscape of cyclin alterations (alt) in non-prostate genitourinary (GU) cancers. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation tissuesequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition). Results: Alterations in any cyclin pathway genes were found in 37.9% of bladder/urothelial, 33.8% of testicular, 25.2% of penile and 24.6% of kidney cancers. Most alterations were copy number changes and frequencies varied substantially for each tumor type (Table). The high number of cases permitted identification of interesting patterns of outliers for each histology (examples: testis rhabdomyosarcoma and leydig tumor, 50% and 54.5% CDK4 alt; ureter urothelial, 17% CCND1 amp; bladder squamous, 41% CDKN2A del; kidney malignant rhabdoid, 90% SMARCB1 alt; urethra urothelial, 14.7% CCNE1 alt). Alterations in possible resistance genes RB1 and CCNE1 were more frequent in bladder cancers (especially with a neuroendocrine component). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alt in cyclin activating and resistance genes (odds ratio for bladder 0.17, p<0.001; OR testis 0.49, p<0.001 and OR kidney 0.45, p<0.001). Conclusions: Cyclin pathway activating and resistance genomic alt are variable in non-prostate GU tumors. Activating alt often occur without simultaneous resistance alt. Our data may inform opportunities for targeted therapy, especially for rare subtypes.[Table: see text]
Serial circulating tumor DNA (ctDNA) measurement to predict progression in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Villamar Dario Martin , Shohdy Kyrillus , Cao Yen Thi Kim Hong , Trieu Janson , Price Kristin Sedgwick , Nagy Rebecca , Molina Ana M. , Tagawa Scott T. , Nanus David M. , Sternberg Cora N. , Sonpavde Guru , Grivas Petros , Vogelzang Nicholas J. , Faltas Bishoy Morris 
Published: February 2020

558 Background: Next-generation sequencing (NGS) of plasma ctDNA is a promising non-invasive method to detect somatic genomic alterations (GAs). We investigated whether serial ctDNA measurements can predict disease progression and map the molecular evolution of advanced UC (aUC) through successive treatments. Methods: We analyzed cohorts from 2 academic centers, WCM and UNLV, with serial (≥2) ctDNA targeted NGS using the Guardant360 panel of 73 genes, ctDNA was collected within four weeks of restaging scans. Non-progressive disease (non-PD) was defined as stable disease or radiological response. Results: Our cohort included 176 individual ctDNA samples (median 3/patient) from 52 patients (38 men), the median age was 69 (range 38-88), 38 pts (73%) had metastatic disease, 20 pts (38.5%) had visceral metastases and 35 pts (67%) received first-line platinum-based combination chemotherapy for aUC. The median number of lines of therapy was 2. 49 pts (94%) had detectable GAs in at least one ctDNA sample. Most commonly identified GAs involved TP53 (67%), PIK3CA, EGFR, and ERBB2 (each in 19%). FGFR3 GAs were identified in 9 pts (17%, 2 FGFR3-TACC3 fusions, and 7 SNVs, including two novel mutations P250R and K650M). The mean variant allele fraction (VAF) significantly decreased in pts with non-PD (80 non-PD events) compared to pts with PD (45 PD events) with a mean VAF decrease of 2.06 % (p< 0.0001). This effect was consistent independent of the number of prior lines of therapy. The mean number of GAs per patient at each time point was significantly decreased in non-PD vs. PD group (2.8 vs. 4.4, p=0.004). Pts with detectable VAF in somatic alterations at any time point during the disease course had shorter overall survival (HR 1.18, 95% CI: 1.08 – 1.28, p<0.0001). Pts with sustained partial or complete responses were more likely to have VAF ≤0.2% suggesting that molecular remission was associated with clinical remission. Conclusions: Serial ctDNA testing is a promising dynamic tool to assess clonal evolution and predict progression in aUC pts.
Microsatellite instability (MSI-H) in metastatic urothelial carcinoma (mUC): A biomarker of divergent responses to systemic therapy.
Authors: Sarfaty Michal , Teo Min Yuen , Al-Ahmadie Hikmat , Funt Samuel Aaron , Lee Chung-Han , Aggen David Henry , Solit David B. , Ratna Neha , Regazzi Ashley Marie , Hechtman Jaclyn Frances , Zehir Ahmet , Rosenberg Jonathan E. , Bajorin Dean F. , Iyer Gopa 
Published: February 2020

566 Background: MSI frequently arises from deficiencies in mismatch repair mechanisms (dMMR) and are associated with higher response rates to anti-PD1/PDL1 checkpoint inhibitors (CPI) in different cancer types, including mUC (Iyer et al, ASCO 2017). Here, we sought to (1) assess the platinum-based chemotherapy response in MSI-H mUC, and (2) present an updated analysis of CPI response in MSI-H mUC from a database of > 1000 sequenced UC. Methods: From an institutional database of UC tumors genomically characterized using the MSK-IMPACT assay, we identified tumors with high MSIsensor score > 10 (MSI-H) for in-depth analysis. MSIsensor has been shown to correlate strongly with MSI status (Middha et al, JCO Precis Oncol 2017). Patient and disease characteristics, as well as response to (1) platinum-based chemotherapy and (2) CPI were analyzed. Results: A total of 1,333 UC from 1,194 pts were sequenced. 26 pts (2%) had an MSI score > 10. Of these, 20 (77%) were male, 17 (65%) were current or former smokers, and 20 (77%) had upper tract UC. 23/26 pts had alterations in MMR genes (MSH2, n = 15; MLH1, n = 6; MSH6 and PMS2, n = 1), 18 of which underwent germline testing which was positive in 14 cases (78%). 10/26 MSI-H patients developed metastatic UC. Six received first-line platinum-based chemotherapy with median PFS of 2.6 months, four with primary progressive disease. Ten patients received CPI in the mUC setting, two of them in combination with non-CTLA4 agents, six as second or third-line therapies, two following recurrence of disease within 12 months of peri-operative chemotherapy, and two as first line therapy. With a median follow-up of 24.3 months, PFS rate was 90% and 77% at 12 and 24 months, respectively, with near-complete or complete response in 9 patients. Conclusions: MSI-H status in UC predicts deep and durable responses to CPI and is associated with inferior chemotherapy responses. CPI should be considered for first-line treatment in this subset of patients. Pts with somatic MSI-H bladder or upper tract UC should be offered genetic testing for Lynch syndrome.
Feasibility of finding circulating tumors cells and assigning PD-L1 receptor status using single-cell technology combined with Celsee Genesis system.
Authors: Alanee Shaheen Riadh , Sharma Vishal , Chow William , Patterson Bruce Kendrick 
Published: February 2020

567 Background: enumerating circulating tumor cells (CTC) may improve our ability to differentiate between localized and metastatic bladder cancer (BC) and predict response to systemic therapies. However, previously used CTC identification platforms had limited utility in managing patients diagnosed with this disease because they lacked the appropriate sensitivity level. Also, they did not report on the PD-L1 receptor status, which is becoming an essential component of modern immunotherapy of BC. Methods: We used a novel device to enrich and retrieve CTCs from blood samples of patients with high grade and low-grade BC, as well as benign conditions, treated with cystectomy by using a microfluidic chip. The Celsee Genesis (Celsee Inc) captures CTCs with high sensitivity and allows the captured CTCs to be retrieved for molecular analysis. It uses the microfluidic chip, which has approximately 56,320 capture chambers. Based on differences in cell size and deformability, each chamber ensures that small blood cells escape while larger CTCs of varying sizes are trapped and isolated in the chambers. PD-L1 expression on the isolated tumor cells was then evaluated using 4-color single-cell technology (IncellDX Inc.) directly on the chip. Results: Ten bladder cancer (5 low grade (LG) and 5 high grade (HG) disease) and two benign bladder pathology patients provided blood samples before their cystectomy. Circulating tumor cells were found in 3 patients (two LG and one HG disease). CTCs were four times higher in the HG sample than in the LG samples. PD-L1 expression was high on CTCs isolated from the HG patient’s blood sample and lower in the two LG blood samples. No CTCs were detected in patients with benign bladder pathology. Conclusions: Our results show the feasibility of using novel, high sensitivity CTC detection and PD-L1 single cell measuring technology in patients with BC. We also show that this technology has a potentially high sensitivity level for detecting CTC in patients with bladder malignancies by detecting low levels of CTCs in low-grade disease. More extensive studies are planned to validate our findings.