bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiotherapy-induced immunogenic effects in bladder cancer.
Authors: Walshaw Richard , Honeychurch Jamie , Roberts Joanne , Swan Jacqueline , Dean Laura , Choudhury Ananya , Illidge Tim 
Published: March 2019

418 Background: Many patients with bladder cancer (BC) undergo radiotherapy (RT) during the course of their treatment. There is emerging evidence that RT can cause immune stimulatory changes within the tumour microenvironment (TME), potentially contributing to its efficacy. We aimed to determine if RT induces immunogenic changes in murine BC cell lines, and develop a pre-clinical model of BC with a TME reflective of de novo tumours in order to test this premise in vivo. Methods: Immunogenic effects of RT were determined using murine vaccination studies with irradiated tumour cells. RT-induced immuno-phenotypic changes in surface antigen expression on tumour cells were ascertained using flow cytometry. An orthotopic BC model was established using MBT2 cells instilled intravesically in C3H/Hen mice, and resulting tumours monitored with ultrasound (US). We used immunohistochemical (IHC) staining to determine the immune contexture of the TME within developing orthotopic tumours. Results: C57BL/6 mice inoculated with irradiated MB49 cells demonstrated improved survival compared to control mice after subsequent rechallenge with viable tumour cells. This effect was not seen in C3H mice implanted with irradiated MBT2 cells. RT led to upregulation of immune stimulatory molecules CD80, MHC I, and Fas on MB49 but not MBT2 cells. Tumours developed in 80% of mice following catheter implant, and visible on US 3-4 weeks after instillation. Profiling of the TME with IHC demonstrated that tumours contained few CD8+ T-cells, but high numbers of myeloid cells. Conclusions: RT induces immune stimulatory effects on murine BC cells, including upregulation of several surface proteins. In future work, we will determine the effects of RT on the TME in the orthotopic model, and correlate these with the expression of various immunogenic cell surface proteins. This may lead to the discovery of a biomarker to predict which patients with BC would benefit from combination of an immunomodulatory agent with RT.
Predictive value of fibroblast growth factor receptor (FGFR) mutations and gene fusions on anti-PD-(L)1 treatment outcomes in patients (pts) with advanced urothelial cancer (UC).
Authors: Santiago-Walker Ademi E. , Chen Fei , Loriot Yohann , Siefker-Radtke Arlene O. , Sun Libo , Sundaram Ramesh , De Porre Peter , Patel Kiran , Wan Ying 
Published: March 2019

419 Background: FGFR alterations have been shown to be associated with immunologically “cold” UC tumors with low immune marker expression and T cell infiltrate, a poorly receptive environment for immune checkpoint inhibitors. Using a real world matched clinical and genomic dataset of pts with advanced UC, we explored their predictive value in pts receiving anti-PD-(L)1 therapy. Methods: The Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) contained full clinical and treatment information and molecular data on a cohort of pts with confirmed advanced UC. The populations of interest are FGFR+ and FGFR- patients determined by the presence or absence of a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS), measured from the start of anti-PD-(L)1 therapy, was analyzed using Kaplan-Meier estimation and Cox proportional hazards models adjusted for left truncation (delayed entry model). Results: 118 pts ( FGFR+ n = 26, FGFR- n = 92) treated with anti-PD-(L)1 therapy for advanced UC were assessed for OS. Median OS for FGFR+ pts who received any line of anti-PD-(L)1 therapy (n = 26) was 3.1 mo vs 6.1 mo for FGFR- pts (n = 92) (hazard ratio [HR] 1.33, 95% CI 0.78-2.26, p = 0.30). For first-line anti-PD-(L)1 therapy, median OS in FGFR+ pts (n = 12) was 4.7 mo vs 11.3 mo for FGFR- pts (n = 28) (HR 1.94, 95% CI: 0.78-4.82, p = 0.15); median OS in second-line were 3.1 mo (n = 12) vs 6.1 mo (n = 47), respectively (HR 1.17, 95% CI 0.53-2.59, p = 0.70). Per multivariate analysis, FGFR+ status appears to be associated with poorer OS in pts treated with any line of anti-PD-(L)1 therapy (HR 1.25, 95% CI 0.71-2.21, p = 0.43). Conclusions: These real-world data suggest that FGFR+ pts following anti-PD-(L)1 therapy for advanced UC may be associated with a trend in poorer overall survival outcome compared with FGFR- pts. These findings are in alignment with treatment history data from BLC2001 (Siefker-Radtke A, et al. ASCO-GU 2018), which showed low response rates to prior anti-PD-(L)1 therapies among FGFR+ pts.
Analysis of FGFR alterations from circulating tumor DNA (ctDNA) and Tissue in a phase II trial of erdafitinib in urothelial carcinoma (UC).
Authors: Santiago-Walker Ademi E. , Moy Christopher , Cherkas Yauheniya , Loriot Yohann , Siefker-Radtke Arlene O. , Motley Clifford , Avadhani Anjali Narayan , OHagan Anne , De Porre Peter , Lorenzi Matthew V. , McCaffery Ian 
Published: March 2019

420 Background: Plasma samples from a Phase 2 study of the pan-FGFR inhibitor erdafitinib in advanced UC patients (pts) with FGFR mutations (mut) or fusions, were tested using next generation sequencing (NGS) for circulating tumor DNA (ctDNA), and results compared to central FGFR status determination from tissue. Methods: FGFR alterations were measured in archival tissue using an RNA-based RT-PCR test and compared with FGFR alterations identified in pre-treatment plasma specimens using the Guardant360 ctDNA test. Sensitivity of the ctDNA test to detect the FGFR alterations identified by RT-PCR from tissue, the proportion of pts with a study-eligible FGFR alteration in ctDNA, and the ability to detect a tissue FGFR alteration in ctDNA in relation to clinical response were assessed. Results: Samples from 155 pts with detectable baseline ctDNA were included. Overall, concordance between ctDNA and tissue-based FGFR results was 56% (87/155): 63% (77/122) for tissue mut-positive pts vs 24% (7/29) in fusion-positive pts. 61% of pts (94/155) were positive for a study-eligible FGFR alteration from blood-based testing in the tissue-positive population. The response rate was 47% (36/77) for patients for which FGFR mutations could be detected in blood (ctDNA- FGFR-positive) compared with 32% (14/44) in patients for which mutations were not detected in blood (ctDNA- FGFR-negative), with an estimated odds ratio of 1.882 (95% CI: 0.866; 4.090) Conclusions: The 63% concordance rate for detecting FGFR mut in temporally unmatched blood and tissue supports potential for patient selection with blood-based testing, while ctDNA FGFR fusion detection may require further optimization. Although differences in clinical response rate were observed between ctDNA- FGFR-positive and negative patients, the results were not statistically significant. Importantly, a proportion of ctDNA-negative pts responded to erdafitinib, indicating that tissue-based testing may be warranted for pts negative for FGFR alterations via blood-based testing. (BLC2001, NCT02365597). Clinical trial information: NCT02365597.
Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer.
Authors: Sweis Randy F. , Golan Shay , Barashi Nimrod , Hill Elle , Andolfi Ciro , Werntz Ryan P. , Bloodworth Jeffrey , Steinberg Gary D. 
Published: March 2019

423 Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for > 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.
Impact of bone metastasis on clinical outcomes in metastatic urothelial bladder cancer (mUC) for patients treated with first-line platinum-based chemotherapy.
Authors: Riromar Jamila Jama Almi , Veitch Zachary William Neil , Sacher Adrian G. , Maganti Manjula , Fallah-Rad Nazanin , Hansen Aaron Richard , Sridhar Srikala S. 
Published: March 2019

431 Background: Prognostic nomograms have identified patients with mUC less likely to benefit from treatment. Yet, analyses have relied on grouped patient variables (ie: bone plus visceral metastases) and refinement is needed. This study aims to evaluate the clinical outcomes of bone metastases (BM) on patients with mUC treated with first-line platinum-based chemotherapy. Methods: Patients receiving first-line platinum-based chemotherapy for mUC at the Princess Margret Cancer Centre from 12/2009-10/2016 were selected from central pharmacy records. Patient and tumor characteristics, in addition to treatment history were collected retrospectively. Oncologist assessed best response (OABR; complete [CR] or partial [PR] response; stable (SD] or progressive [PD] disease) was evaluated by chart review. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier (log-rank). Overall response rate (ORR) was calculated from OABR. Multivariable analysis (MVA) was performed using Cox-regression. Significance was evaluated at the p < 0.05 level. Results: Of 112 patients receiving platinum-based chemotherapy, 62 (55%) had mUC. Most patients were male (73%), had ECOG PS of 0-1 (71%), and de novo metastases (23%). Patients received a median of 5 chemotherapy cycles (range 1-8), and median follow-up was 12.7 months. Number of organs involved with metastases varied (1 = 32%; 2 = 45%; 3+ = 23%); with lymphnode (77%), bone (37%), and lung metastases (34%) frequently involved. Median PFS (months) was shorter (p < 0.05) in patients with BM (5.6; 95%CI:2.7-7.0) compared to no BM (8.0; 95%CI:6.5-9.5). Median OS (months) was shorter (p < 0.05) in patients with BM (8.9; 95%CI:7.2-15.9) compared to no BM (16.1; 95%CI:10.5-23.4). ORR was lower for those with BM (22%) compared to no BM (56%). MVA using BM and prognostic nomogram criteria showed significance for ECOG 2+ (HR = 2.72; p < 0.05) with a trend towards significance for BM (HR = 1.85; p = 0.06). Conclusions: mUC patients with BM have lower response and inferior survival by log-rank. This could have direct implications for clinical decision making and stratification of factors in clinical trials.
Tumor mutational burden (TMB) and BCG responsiveness in high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Bastos Diogo Assed , Lima Mariana , Mattedi Romulo Loss , dos Santos Filipe Ferreira , Buzatto Vanessa , Barreiro Rodrigo , Ribeiro-Filho Leopoldo , Cordeiro Mauricio , Amano Mariane , Souza Jussara Michaloski , Bettoni Fabiana , Galante Pedro Alexandre Favoretto , Dzik Carlos , Nahas William Carlos , Camargo Anamaria Aranha 
Published: March 2019

442 Background: Despite optimal management of NMIBC with transurethral resection of bladder tumor (TURBT) and intravesical BCG therapy, a significant proportion of patients (pts) will eventually present with disease recurrence or progression. To date, there is no validated predictive biomarker to guide patient selection for the most appropriate therapy in this setting. Methods: We retrospectively identified pts with high-risk NMIBC treated with TURBT, repeat TUR and intravesical BCG (≥ 6 instillations) from 2009 to 2016. Patients were classified as BCG-responsive (BCG-R) and BCG-unresponsive (BCG-UR) based on the International Bladder Cancer Group criteria. Whole exome sequencing was performed using archival FFPE tumor tissue from pre-BCG TURBT samples. Association of genomic variables and outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. Results: Thirty-five patients were included (BCG-R = 17, BCG-UR = 18). Median follow-up was 46 months for BCG-R and 52 months for BCG-UR pts. The majority of pts was male (91.4%), former smoker (60%), and presented with high-grade urothelial carcinoma (85.7%) and/or T1 staging (71.4%). Median time for relapse and progression was 10.5 and 19 months, respectively, in the BCG-UR group. In this cohort, TMB was significantly different in BCG-R and BCG-UR groups, with a median TMB of 5.53 +- 4.60 and 3.17 +- 1.82 mutations/Mb, respectively ( P= 0.045). TMB was also associated with relapse-free survival (RFS), with a median RFS of 38 and 15 months in high versus low TMB groups, respectively ( P= 0.0092). Intratumoral genetic heterogeneity assessed by mutant-allele tumor heterogeneity (MATH) was not statistically different between the groups, with a median MATH score of 31.8 and 21.9 for BCG-R and BCG-UR ( P= 0.14), respectively. On multivariate analysis, age and TMB were independently associated with RFS. Conclusions: In this exploratory biomarker study, high TMB was associated with benefit from immunotherapy with BCG for NMIBC. The identification of predictive biomarkers in this setting is an important unmet need and integrative analysis of TMB with other potential predictive biomarkers should be assessed in larger datasets.
Evaluation of prognostic effects of MSI, PD-L1 and TIL in resected bladder cancer.
Authors: Tural Deniz , Akar Emre , Baytekin Halil Firat , Tugcuoglu Volkan 
Published: March 2019

465 Background: The aim of the study was evaluating prognostic significance of tumor infiltrating lymphocytes (TIL), microsatellite instability (MSI) and programmed cell death ligand-1 (PD-L1) expression which are used as predictive biomarkers in immunotherapy. Methods: Clinic and pathologic features of bladder cancer patients who were underwent radical cystectomy were retrospectively analyzed from patients’ records in this single-center study. PD-L1, PD-L1 in TIL, PMS2, MSH2, MSH6 and MLH1 immunohistochemistry staining were carried out to archived resected tumor specimens of the eligible patients. MSI was evaluated according to existing of PMS2, MSH2, MSH6 and MLH1. Results: Fifty-six males (91.8%) and 5 females (8.2%) of total 61 patients were eligible for the study. Median age was 61.72 (35-81). PD-L1 expression in tumor cells and PD-L1 expression in TIL were positive in 14,8% (n = 9) and 16.4% (n = 10) of total 74 patients, respectively. MSI was high in 15 patients (24.6%). Intratumoral TIL rate was < 10% in 49 patients (80.3%) while > 10% in 12 patients. (19.7%) In Chi-square test, there was no statistically significant relationship between PD-L1, PD-L1 in TIL, MSI and TIL rate and patients’ characteristics including sex, stage, pathologic grade and lymph node status. Three-years overall survival (OS) rate was calculated as 43%. Univariate analysis did not reveal any significant difference in 3-years OS in PD-L1 expression in tumor, PD-L1 expression in TIL and TIL rate > 10% . (p = 0.822, p = 0.638, p = 0.318; respectively ). There was a positive trend with MSI high patients and OS (p = 0.089). At also; age and stage showed statistically significant difference in multivariate analysis. (p = 0.023, p = 0.011, respectively). Conclusions: This study revealed that there is no prognostic significance of PD-L1 and TIL. However, there are positive trend between OS and MSI, which is proven as predictive biomarker of immunotherapy, in patients who were followed with same treatment and follow-up approach in single center. These results must be corroborated with large and prospective investigations in order to better understanding biology and behavior of bladder cancer.
Durable clinical benefit from combination ipilimumab (IPI) and nivolumab (NIVO) in anti-PD-1 therapy resistant, platinum resistant metastatic urothelial carcinoma (mUC).
Authors: Keegan Niamh M. , Funt Samuel Aaron , Kania Brooke Elizabeth , Iyer Gopa , Clement Jessica Mary , McCoy Asia S. , Hettich Grace , Ziv Etay , Maher Colleen Anne , Nair Suresh , Panageas Katherine , Bluth Mark J. , Wong Phillip , Wolchok Jedd D. , Rosenberg Jonathan E. , Bajorin Dean F. , Callahan Margaret K. 
Published: March 2019

481 Background: Overcoming resistance to anti-PD-1 therapy in UC patients (pts) is of major interest given the modest single agent response rates for pts with mUC. Herein we report the outcome of combined NIVO and IPI in pts who progressed on single agent NIVO. Methods: This prospective, open label, adaptive study treated platinum resistant mUC pts with NIVO monotherapy with the designated intent to add IPI at disease progression. RECIST 1.1 assessments were performed every 6 wks for 24 wks then every 12 wks. Primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS) and possible associations between clinical endpoints and tumor genomic characteristics. Next generation sequencing (NGS) was performed to assess DNA Damage Response (DDR) gene mutations and Tumor Mutation Burden (TMB). Results: To date, 21 pts who progressed after NIVO monotherapy have received IPI plus NIVO. ORRs to prior NIVO monotherapy were variable; partial response (PR = 4/21, 19%), stable disease (SD = 6/21, 29%) and progressive disease (PD = 11/21,52%). 57% (12/21) had visceral metastases. For IPI + NIVO the ORR was 19% (PR: n=4, CR: n=0) and duration of response >12 mo in a subset; 2 pts with PR remain on treatment (3+, 5+ mo), 1 pt has an ongoing PR (13+ months) after stopping treatment due to toxicity. Responding disease sites include node, liver and lung. Immune-related toxicity ≥ G3 seen in 9 pts (43%), of whom 4 (44%) had disease control (PR+SD≥3mo). No correlation detected between clinical outcome and TMB or DDR mutations. Conclusions: IPI plus NIVO responses can be seen in pts with NIVO resistance and the benefit from combined checkpoint blockade can be prolonged. Immune related toxicity frequently accompanied disease control. TMB and DDR were not associated with benefit in this small cohort; immune correlative analyses are ongoing. Clinical trial information: NCT02553642. [Table: see text]
The PRIMETEST trial: Interim analysis of a phase II trial for primary retroperitoneal lymph node dissection (RPLND) in stage II A/B seminoma patients without adjuvant treatment.
Authors: Albers Peter , Hiester Andreas , Grosse Siemer Robert , Lusch Achim 
Published: March 2019

507 Background: We thought to evaluate progression-free survival of stage II A/B seminoma patients (pts) undergoing primary retroperitoneal lymph node dissection (RPLND) without adjuvant treatment. Aim is to present interim data of a feasibility study and a phase II trial. Methods: Prior to the phase II study, 9 patients have been treated within a pilot feasibility study. After IRB approval, additional 12 patients from 3/2016 to 9/2018 within the prospective phase II trial were accrued. All patients received primary retroperitoneal lymph node dissection (open or daVinci assisted) for stage IIA/B seminoma without adjuvant treatment. The data was analyzed for peri- and postoperative outcome including recurrence free survival. The trial will have to accrue 30 pts and was designed to exclude a > 30% recurrence to standard treatment. Results: Since 5.2014 twenty-two patients with seminomateous germ cell tumor have been included in both studies, including one patient with an atypical inguinal recurrence and one patient with a 6 cm marker negative recurrence (clinical stage IIC). Primary RPLND was performed in 4 patients with initial CSIIA. 14 and 4 patients experiences a recurrence under surveillance and after carboplatin adjuvant treatment, respectively. Mean tumor size was 2.6 cm with a mean OR time of 134 min and a mean blood loss of 70 cc. One patient after DaVinci RPLND developed a ureteral stricture requiring ileal ureter substitute. The mean follow-up is 24 month (range 1-51 months), 17/22 patients (77%) are free of recurrence. 5/22 (23%) developed a recurrence (4x outside field and 1x inside field) with a mean time to recurrence of 4.5 months. All patients received salvage treatment (4x CTX and 1x radiotherapy) and are currently recurrence free. Conclusions: Primary RPLND in stage IIA/B seminoma patients is an experimental treatment approach in order to reduce long term toxicity and secondary malignancies. Interim results of this strategy justifies continuation of the study. This kind of surgery should only be performed within clinical trials in high volume referral centers. Clinical trial information: NCT 2015053664.